Oxidative Medicine and Cellular Longevity

Oxidative Medicine and Cellular Longevity / 2020 / Article

Review Article | Open Access

Volume 2020 |Article ID 1234059 | https://doi.org/10.1155/2020/1234059

Jing Guo, Hui Juan Zheng, Wenting Zhang, Wenjiao Lou, Chenhui Xia, Xue Ting Han, Wei Jun Huang, Fan Zhang, Yaoxian Wang, Wei Jing Liu, "Accelerated Kidney Aging in Diabetes Mellitus", Oxidative Medicine and Cellular Longevity, vol. 2020, Article ID 1234059, 24 pages, 2020. https://doi.org/10.1155/2020/1234059

Accelerated Kidney Aging in Diabetes Mellitus

Academic Editor: Gianna Ferretti
Received30 Mar 2020
Revised25 May 2020
Accepted25 Jun 2020
Published28 Jul 2020

Abstract

With aging, the kidney undergoes inexorable and progressive changes in structural and functional performance. These aging-related alterations are more obvious and serious in diabetes mellitus (DM). Renal accelerated aging under DM conditions is associated with multiple stresses such as accumulation of advanced glycation end products (AGEs), hypertension, oxidative stress, and inflammation. The main hallmarks of cellular senescence in diabetic kidneys include cyclin-dependent kinase inhibitors, telomere shortening, and diabetic nephropathy-associated secretory phenotype. Lysosome-dependent autophagy and antiaging proteins Klotho and Sirt1 play a fundamental role in the accelerated aging of kidneys in DM, among which the autophagy-lysosome system is the convergent mechanism of the multiple antiaging pathways involved in renal aging under DM conditions. Metformin and the inhibitor of sodium–glucose cotransporter 2 are recommended due to their antiaging effects independent of antihyperglycemia, besides angiotensin-converting enzyme inhibitors/angiotensin receptor blockers. Additionally, diet intervention including low protein and low AGEs with antioxidants are suggested for patients with diabetic nephropathy (DN). However, their long-term benefits still need further study. Exploring the interactive relationships among antiaging protein Klotho, Sirt1, and autophagy-lysosome system may provide insight into better satisfying the urgent medical needs of elderly patients with aging-related DN.

1. Introduction

The increasing global morbidity of type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) has provoked research efforts to overcome the growing prevalence of diabetic nephropathy (DN), which has been a global catastrophe due to limited efficacy with existing therapies and serious financial burden [13]. It is urgent to explore the unknown mechanisms underlying DN and discover curative efficient therapies.

As is well known, both T2DM and CKD are aging-related diseases. The morbidity of DM in people over 65 years old is more than twice that of people over 20 years old [1], and aging is a key factor attributing to nephron loss and resulting in CKD [4].

DM has been considered to be an inducer of accelerated cellular senescence and has been associated with aging-related cardiovascular diseases and kidney diseases due to high glucose levels [5]. However, the aging in a tissue-specific manner remains rarely explored. Globally, DM has been the leading cause of end-stage renal disease (ESRD), especially in elders [3, 6, 7]. Feasible histopathological patterns of individuals often imply the presence of other pathogenic factors, such as aging-related nephropathy, resulting in the complicated and difficult diagnosis and treatment of type 2 DN [8]. Thus, under the double risk factors of high glucose and aging, it is hypothesized that renal aging plays a vital role in the development of DN. Herein we will discuss current knowledge on renal aging-related mechanisms and potential therapeutic targets of DN.

2. The Role of Accelerated Kidney Aging in DN

Kidney aging is a complex process that interacts with many diseases, especially those that are more prevalent in the elderly population. Kidney aging is manifested in the decline of glomerular filtration rate (GFR), which is also the physiological characteristic of CKD [9, 10]. The GFR decreases by about 5%–10% per decade after 35 years of age, and the elderly, 70–75 years old, had 48% fewer intact nephrons than the younger patients aged 18–29 years old [11, 12]. It is often difficult to distinguish between chronological change and pathological changes, but some studies have focused on accelerated aging as a potential target to retard the process of renal diseases, including DN [13, 14].

In kidneys with premature aging due to the morbid state such as IgA nephropathy [13], the above characteristics may not be necessarily related to chronological change. For DN, the incidence of kidney disease in diabetic individuals partly depends on the aging-related nephron loss [15]. Except for the functional change of decreasing GFR, the structural changes are also observed as pathologic reduction in kidney size and renal histomorphology changes, including glomerulosclerosis, interstitial fibrosis, and tubular atrophy macroscopically and compensatory hypertrophy of renal cells, glomerular basement membrane (GBM) thickening, podocyte loss, and tubular epithelial cell (TEC) shrinking microscopically [16].

It has been demonstrated that the kidney appears aging phenotype which represents a proximate mechanism by which the kidney is damaged in DN [17, 18], leading to a complicated and difficult diagnosis and treatment of type 2 DN. Thus, accelerated kidney aging may be an important part of the pathogenesis of DN (Figure 1). However, the cellular and molecular mechanisms of kidney aging in diabetic individuals are complicated and poorly understood.

3. Factors Associated with Accelerated Kidney Aging in DN

DN is the renal manifestation of the hyperglycemia-driven process in vulnerable sites along with retinopathy. Multifactors are posed with DN beyond high glucose, such as oxidative stress and activation of the renin-angiotensin-aldosterone system (RAAS) [15]. Accumulation of advanced glycation end products (AGEs) [19] and inflammation also contribute to the process of DN [20]. Similarly, kidney aging is associated with clinical factors such as DM and hypertension, as well as tissue factors including angiotensin II, AGEs, oxidative stress, and so on [21]. Hence, herein we focus on AGEs, hypertension, inflammation, and oxidative stress in diabetic kidneys.

AGEs, which are accumulated in multiple tissues during aging, provide information of a nonenzymatic reaction of proteins and carbohydrates that can be detected with an increased level in each related organ of patients with DM [22]. AGEs, as a result of pathologically increased glycation due to chronic hyperglycemia, have a variable “pathological expression” in DM, kidney failure, and tissue aging [23]. Interestingly, reducing AGEs extends the lifespan of yeast [24]. Hence, AGEs can be a biomarker of aging and may lead to renal lesions in DM related to kidney aging [25]. In hyperglycemic circumstances, the accumulated AGEs induce the accelerated aging of kidney dysfunction by inducing podocyte damage and apoptosis of mesangial cells and the expression of transforming growth factor-β (TGF-β), the latter of which plays a pivotal role in fibrogenesis [26, 27]. AGEs stimulate the activation of the receptor for AGEs (RAGE), which induces oxidative stress and cellular dysfunction. In the kidney, the RAGE-AGE activation also contributes to the induction of oxidative stress, endoplasmic reticulum (ER) stress inflammatory, and fibrotic responses by activating different intracellular signaling pathways, such as phosphatidylinositol 3 kinase/protein kinase B (PI3K/Akt), mitogen-activated protein kinase/extracellular regulated protein kinases (MAPK/ERK), and nuclear factor kappa-B (NF-κB), all of which lead to functional and structural damages of kidneys, as well as premature aging [19, 28].

Hypertension is one of the clinical symptoms of DN due to the dysfunction of the RAAS, and RAAS inhibitors have been considered to be the most effective therapy for DN [29]. In the aging kidney, the RAAS is related to glomerular and tubular damage via oxidative stress and/or downregulating antiaging proteins, such as Sirtuins and Klotho [30, 31]. AGEs stimulate angiotensinogen production in renal proximal tubular cells, which results in inappropriate activation of RAAS and exacerbates the development of diabetic-related kidney lesions [32]. Thus, these findings suggest that the abnormal activation of RAAS aggravates kidney damage and may lead to accelerated senescence in DN.

Oxidative stress (OS) is considered a major factor in the pathogenesis of DN due to its contribution to hyperglycemia and hypertension [33]. OS contributes to aging as a result of causing increased damage to important cellular targets, increasing mutation rates, and inducing growth inhibition [34]. In diabetic kidneys, the main sources of OS include nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation [35], mitochondrial dysfunction [36, 37], xanthine oxidase pathway abnormality, cyclooxygenase pathway dysregulation, and endothelial nitric oxide synthase uncoupling [38]. These sources of OS contribute to a range of harmful intracellular events, including DNA damage within the nucleus and mitochondria, and ultimately result in the death of renal intrinsic cells via apoptosis that ER stress and cellular senescence contribute to [39, 40]. Additionally, high glucose- (HG-) induced reactive oxygen species (ROS) production results in increased TGF-β1 expression, which is the core link of renal fibrosis in diabetic kidneys and results in the epithelial-mesenchymal transition [41]. Recent studies have reported that P66 plays a key role in the pathogenesis of DN because of its relation to OS. ROS metabolism was substantially increased in HG-induced mesangial cells in association with more cell death via apoptosis, as well as the acquisition of a senescent phenotype and a homozygous mutation at the P66 locus that confers delayed aging phenotypes in the diabetic kidneys [18]. The abnormal expression of p66 may have a correlation with the protein kinase C (PKC) β activation and then regulate NADPH oxidase, which could further promote the activation of OS [42].

Inflammation is the both cause and consequence of accelerated aging leading to renal damage [43, 44]. Inflammation plays an important role in the genesis of DM as well as in the development of diabetic complications, including DN. The metabolic alterations with the accumulation of toxic products, such as AGEs and hemodynamic factors and the activation of RAAS, enhance inflammation of the kidney [45, 46]. Excessive ROS production in kidney tissues activates inflammation-related signaling pathways, such as PKC, MAPK, and NF-κB, and leads to the production of a large number of cytokines and growth factors that trigger the onset of DN. This process then causes the deposition of the extracellular matrix (ECM) in glomeruli, the differentiation of tubular epithelial cells (TECs), and the interstitium and an increase in the synthesis of glomerular fibronectin (FN) proteins in the mesangial region [47]. Proteinuria, a marker of renal lesions, aggravates the local microinflammatory response and enhances interstitial cellular infiltration, leading to the overexpression of mesangial matrix production, glomerular basement membrane (GBM) thickening, and glomerulosclerosis [48]. Persistent microinflammation is increased in the aging kidney and provides potential mechanistic links between the epigenetic landscape of aging and renal dysfunction [49, 50].

Taken together, in diabetic kidneys, multiple stresses, such as AGEs accumulation, hypertension, oxidative stress, and inflammation, induce a negative environment that accelerates senescence that is manifested in renal functional decline and aberrant structural changes (Figure 2).

4. Cellular Senescence and Kidney Aging in DN

It has been reported that cellular senescence plays a vital role in the aging and diseased kidney [51]. Cellular senescence can be widely observed in the aging kidney as an important cellular process that contributes to age-related kidney changes and CKD progression [52]. Besides, it is also involved in kidney aging. During aging, cellular senescence can be independently induced by stresses such as oxidative stress, which is called stress-induced premature senescence through p16INK4/retinoblastoma (Rb) or p53/p21Cip1 pathway. In kidneys, senescent cells are manifested in the arrest cell cycle, imbalance of apoptosis and proliferation, and senescence-associated secretory phenotype (SASP), leading to kidney aging by increasing sensitivity to injury and reducing repair after injury [53, 54]. In addition, clearance or depletion of senescent cells can relieve age-related damage and dysfunction in kidneys [51]. The conversion of a senescent phenotype is a significant step that underlies the pathogenesis of renal lesions as an early response to DM, which might be a target to retard DN progression [55].

Senescent cells provoke permanent cell cycle arrest by triggering cyclin-dependent kinase (CDK) inhibitors which mediate renal injury in DN. Studies on both progeroid and naturally aged mice showed that selective elimination of p16INK4-expressing senescent cells increased health and lifespan [56, 57], and in humans, p16INK4was shown as one of the top genes exhibiting elevated expression with age in multiple tissues, including kidneys [58]. In diabetic kidneys, accelerated senescent phenotypes were mainly observed in tubular cells and podocytes, and the positive correlation between glomerular p16INK4 with proteinuria indicated that glomerular cellular senescence takes partly responsibility for altered permeability [17]. AGE-induced p16INK4 expression and premature senescence were successfully relieved by an ER stress inhibitor and cyclic AMP-dependent transcription factor (ATF) 4 gene silencing in TECs of DN [14]. The expression of p21Cip1 was increased with an upregulation in senescence-associated β-galactosidase (SA-β-gal) staining in TECs [55], and the changes could be suppressed by insulin therapy. However, senescence induced by high glucose was inhibited in p21Cip1 knockdown mice, indicating that aging in renal TECs is mediated by a p21Cip1-dependent pathway [59]. TGF-𝛽1 induces p21Cip1 dependent hypertrophy of mesangial cells and plays an important role in the pathogenesis of chronic kidney diseases, including DN. TGF-𝛽1 increases p21Cip1 gene expression in renal mesangial cells and elevates the recruitment of the H3K4 methyltransferase SET7/9 to the p21Cip1 gene promoter [60]. It has been reported that there exists a complex crosslink between ER stress and p21Cip1 signaling in aging-related diseases [61]. In diabetic TECs, the ER stress marker is expressed at a higher level compared to that of controls and is positively correlated with enhanced SA-β-gal-positive cells and colocalization with RAGE. ER stress-mediated premature senescence is dependent on p21Cip1 activation, because the ER marker and p21Cip1 were colocalized in the same diabetic TECs in vivo and in vitro. Moreover, inducers of ER stress directly cause premature senescence of TECs by p21Cip1 activation. Thus, p21Cip1 signaling plays a deterministic role, which is promoted by RAGE, in the premature senescence of TECs that is mediated by the activation of ER stress [62]. P27Kip1 is another member of CDK2 inhibitors. Chronic hyperglycemia induces hypertrophy and damage to podocytes and mesangial cells related to p27Kip1 [63, 64]. In Type I DM, p27Kip1 knockout mice exhibited milder renal lesions compared to that of p27Kip1 +/+mice due to the regulation of TGF-β; additionally, angiotensin receptor blocker treatment alleviated renal hypertrophy by inhibiting p27Kip1 expression [64, 65]. Senescent phenotypes might have individualized expression in different renal cells, but controversial results have still been reported. For example, some studies showed that p16INK4 expression increased in diabetic TECs, whereas other studies have reported that overexpression of p21Cip1 but not other CDK inhibitors, such as p16INK4 and p27Kip1, is increased due to hyperglycemia [59]. These discrepancies might be related to the different stages of DN in different studies. However, further studies still need to further account for these discrepancies in the future.

Another feature of senescent cells is senescence-associated secretory phenotype (SASP). SASP is a significantly distinctive feature of senescent cells that includes diverse cytokines, chemokines, growth factors, proteases, and lipids, which may promote inflammation in aging-related diseases [66]. NF-κB is activated by DDR and p38 AMP-activated protein kinase (AMPK) in the production and secretion of SASP, and the main components of SASP during the mature period are soluble cytokines, such as C-X-C-motif chemokine ligand-1/2 (CXCL-1/2), interleukin- (IL-) 8, IL-1, matrix metalloproteinases (MMPs), and ECM proteins, that may contribute to the accumulation of ECM and renal interstitial fibrosis in CKD [66]. Premature senescence of intrarenal and extrarenal cells appearing with the overexpression of SASP leads to aggregative kidney aging and disease progression. The similarities of SASP and the CKD-associated secretory phenotype (CASP) have been compared with one another and may present a link between CKD and renal cellular senescence [67]. Considering the microinflammation in the mechanisms of DN, we summarize the relative specific secretory phenotypes in DN compared with those in CASP (Table 1).


SASP factorsSecretory profile for senescent cells [67, 227]DN-associated secretory phenotype

Cytokines
 IL-1α,-1β,-2,-4,-6,-10,-13-17,-18,-20[228239]
 TNF-α[229, 232, 233, 237239]
 TWEAK[240]
 ICAM-1[230, 233, 241244]
 VCAM-1[232]
 Chemokines
 CXCL-1,-5,-7[233, 243]
 CCL-2,20[233]
 CCL-4,-5[230, 243, 245]
 IL-8[236]
 MCP-1[235, 236, 238, 243246]
 MIP-1,-2[243, 244]
 Eotaxin×[241]
Other inflammatory factors
 GM-CSF[233]
 G-CSF×[234, 237]
 IFN-γ×[229]
Growth factors and regulators
 IGFBP-3, -7[247, 248]
 TGF-β[96, 117, 234, 242, 246]
 VEGF[230, 233]
 PDGF[233]
 FGF-2, 23[249, 250]
Proteases and regulators
 MMP-2, -9,[232, 251, 252]
 TIMP-1↓or ×[251]
 TIMP-2[242]
 PAI-1[230, 232, 253]
 Cathepsin B[106, 117]
Insoluble factors (ECM)
 Fibronectin[239, 246, 253]
 CollagensAltered[231, 234, 239, 242, 246, 253]
Other factors
 iNOS[235]
 ROSAltered[96, 239]
 COX-2[235]
 NOX-4[254]
 SOD[96, 235, 238, 239, 254]
 MDA[96, 235, 238, 239, 254]

Abbreviations: SASP: senescence-associated secretory phenotype; IL: interleukin; TNF-α: tumor necrosis factor α; TWEAK: apoptosis of tumor necrosis factor-like weak inducer; ICAM-1: intercellular adhesion molecule 1; VCAM-1: vascular cell adhesion molecule 1; CXCL: C-X-C-motif chemokine ligand; CCL: C-C-motif chemokine ligand; MCP: monocyte chemoattractant protein; MIP: macrophage inflammatory protein; GM-CSF: granulocyte-macrophage colony-stimulating factor; G-CSF: granulocyte colony-stimulating factor; IFN-γ: interferon-γ; IGFBP: insulin-like growth factor binding protein; TGF-β: transforming growth factor -β; VEGF: vascular endothelial growth factor; PDGF: platelet-derived growth factor; FGF: fibroblast growth factor; MMP: matrix metalloproteinase; TIMP: tissue inhibitors of metalloproteinases-1; PAI-1: plasminogen activator inhibitor -1; iNOS: inducible nitric oxide synthase; ROS: reactive oxygen species; COX-2: cyclooxygenase-2; NOX-4: NADPH oxidase-4; SOD: superoxide dismutase; MDA: administration; Upward arrows, crosses, and downward arrows show secretory increase, no change and decrease in senescence, respectively.

Telomere shortening is another cause of triggering senescence. It has been shown that telomeric DNA is lost in the aging kidney of humans [68], and the shortening of telomere length may be associated with CKD occurrence and/or decline of kidney function [69]. In cultured TECs, high glucose accelerated telomere shortening may be mediated by oxidative stress because of hyperglycemia [17]. For mesangial cells, senescence was associated with telomere attrition induced by high glucose via the p53-p21-Rb signaling pathway. [70]. These results may contribute to a new strategy for the treatment of DN.

5. Main Cellular and Molecular Mechanisms of Accelerated Kidney Aging in DN

Molecules and signaling pathways related to the mechanisms of accelerated kidney aging in DM remain multiple and complicated. Herein, we review the mechanisms in four aspects (including Sirt1, Klotho, autophagy, and lysosome) because of their core and inevitable role related to the kidney aging in DM.

5.1. Sirt1 and Kidney Aging

Sirt1 protein expression can be detected in the normal kidney, and its expression level is decreased in the diabetic kidney [71, 72]. The decline of Sirt1 expression in diabetic-kidney tissue leads to mitochondrial damage and OS and plays a vital role in renal premature senescence by impairing antistress capacity and accumulating renal lesions [73]. The podocyte-specific loss of Sirt1 not only aggravates diabetic kidney injury but also leads to aggravated aging-induced glomerulosclerosis and albuminuria. This phenomenon is associated with reduced activation of transcription factors, such as peroxisome proliferator-activated receptor- (PPAR-) α coactivador-1 (PGC-1α)/PPARγ, Foxo3, Foxo4, and p65 NF-κB, via Sirt1-mediated deacetylation [71](Figure 3(b)).

Caloric restriction was first proposed to be associated with antiaging in 1934, and Sirt1 has been reported as an antiaging molecule related to caloric restriction of aging-related diseases [74, 75]. In fatty diabetic Wistar rats, dietary restriction ameliorated renal abnormalities and decreased expression of Sirt1, increased expression of acetylated-NF-κB, and impaired autophagy. These results demonstrated that dietary restriction-mediated Sirt1 restoration exerted anti-inflammatory effects and improved autophagy dysregulation, which resulted in the amelioration of renal injuries in DM [76]. AGEs reduced the Sirt1 level but enhanced the expressions of FN and TGF-β1 in mesangial cells. The overexpression of Sirt1 further increased the nuclear accumulation of nuclear factor E2-related factor 2 (Nrf2) and promoted heme oxygenase 1(HO-1) and superoxide dismutase (SOD) 1 levels, whereas it decreased ROS, FN, and TGF-β1 levels induced by AGEs (Figure 3(b)). Thus, Sirt1 showed resistance against oxidative stress-mediated diabetic renal fibrosis [77]. The same results could also be demonstrated in human renal TEC line HK2 cells [78]. Sirt1 regulates mitochondrial biogenesis and turnover in relation to the deacetylation of PGC-1α [79]. HG accelerated mitochondrial dysfunction and downregulated Sirt1 expression. Activation of the Nrf2- antioxidant response element (ARE) antioxidative pathway ameliorates hyperglycemia-mediated mitochondrial dysfunction partly through Sirt1 [8082] (Figure 3(b)).

These findings highlight that Sirt1 plays an important role in antisenescence in DN, by targeting members of SASP (e.g., NF-κB and TGF-β), as well as by relieving renal inflammation, fibrosis, and oxidative stress to alleviate mitochondrial damage of renal cells.

5.2. Klotho and Kidney Aging

Klotho is an aging suppressor gene that encodes a single-pass transmembrane protein with an extracellular portion, exhibits multiple pleiotropic effects, and is found in two forms: an intermembrane form and a secreted form [83]. The membrane klotho forms a complex with fibroblast growth factor 23 (FGF23) receptor, and this complex mediates phosphate homeostasis and vitamin D metabolism. Secreted Klotho acts as a humoral factor targeting distant organs with pleiotropic activities consisting oxidative stress regulation, growth factor signaling, and ion homeostasis and can be detected in blood, urine, and cerebrospinal fluid [84, 85].

In mice, the overexpression of Klotho extends lifespan, whereas mutations to the Klotho gene shorten lifespan. In humans, serum Klotho levels are lower in individuals that are 40 years old or older [86]. Klotho is predominantly expressed in renal TECs and is equipped with a variety of biological functions. The antiaging role of Klotho is related to its downregulation of cytokines and growth factor signaling, such as interferon-γ (IFN-γ), insulin-like growth factor-1 (IGF-1), and TGF-β, and works by inducing antioxidative stress mediated by insulin, via IGF-1 signaling [86] (Figure 3(a)). Furthermore, it is related to iron imbalance [85]. The level of Klotho expression in diabetic patients and mice was significantly reduced, which was related to increased urinary calcium excretion [87]. Klotho levels were decreased with increasing albumin excretion in patients [88] and were significantly associated with a decline in eGFR [89]. These findings are similar to those of other studies [90]. Thus, Klotho may be a predictive biomarker for the progression of DN.

Klotho was observed to attenuate renal fibrosis in DN. The expression of Klotho in renal tubules declined in streptozotocin- (STZ-) diabetic rats, and Klotho alleviated HG-induced profibrotic genes, TGF-β signaling, and cell hypertrophy in rat renal fibroblast cell line NRK-49F cells. Moreover, Klotho attenuated HG-induced FN expression and cell hypertrophy via ERK1/2 and p38 kinase-dependent pathways [91] (Figure 3(a)). In addition, in spontaneously diabetic mice, it was also observed that the upregulation of Klotho attenuated renal hypertrophy, albuminuria, glomerular mesangial expansion, as well as attenuated glomerular macrophage infiltration and suppressed proinflammatory cytokines [92]. Additionally, Klotho downregulated early growth response factor 1 by inhibiting TGF-β1/Smad3 signaling in HG-induced human mesangial cells to combat renal fibrosis [93] (Figure 3(a)).

Klotho has also been shown to be involved in anti-inflammation in DN. In db/db mice, renal Klotho gene and protein expression were significantly downregulated, and overexpression of Klotho repressed NF-κB activation and subsequent production of inflammatory cytokines in response to TNF-α stimulation. These findings suggest that Klotho serves as an anti-inflammatory modulator that negatively regulates the production of NF-κB linked inflammatory proteins [94] (Figure 3(a)).

Klotho deficiency may be associated with increased OS, and anti-OS is a potential treatment target for DN. OS is more serious in patients with DN compared to that of the healthy controls [95]. AGE-triggered cellular senescence was at least partially due to the activation of OS, and Klotho overexpression protected TECs from injury induced by AGEs and H2O2; thus, Klotho can attenuate the OS [96].

Klotho inhibits the progression of DN by attenuating vascular endothelial dysfunction, calpain activation, and chronic inflammation. In addition, Klotho has been shown to inhibit diabetic renal tubular hypertrophy by inhibiting IGF-1 signaling [92, 97] (Figure 3(a)). Taken together, Klotho participates in multiple antiaging pathways to protect renal function in DN.

5.3. Autophagy and Kidney Aging

Autophagy is a degradation and recycling system in the process of growth, development, and aging. Autophagy has two main roles in the cell: (1) self-digestion in nutrient-deficient conditions to achieve the reuse of energy; (2) degradation of damaged or excess organelles and macromolecules to maintain cellular metabolism under stress [98]. A large number of studies have demonstrated that autophagy inhibition increases with aging and progresses in aging-related diseases [99, 100]. As a convergent mechanism of multiple longevity models, the activity of basal autophagy is elevated in many longevity paradigms of lifespan extension or delayed aging [101]. Autophagy appears to be a causal effector of existing antiaging manipulations such as the longevity drugs, such as resveratrol, rapamycin, and spermidine [102]. Rapidly accumulating evidence has revealed that autophagy is involved in renal physiology, kidney aging, and several kidney diseases, and plays a renoprotective role in various animal models.

Notably, serum levels of Beclin-1, a regulator of autophagy, are reduced in patients with DM and DN. Beclin-1 is also related to the stage of DN and correlates with the degree of albuminuria, which indicates autophagy inhibition in patients with diabetic renal lesions [103]. In addition, the basal activity of autophagy is inhibited in intrinsic cells in diabetic kidneys [104]. The potential mechanisms might be due to the appearance of oxidative stress and inflammation secondary to stimuli such as AGEs and urinary proteins [105107]. Autophagy regulates TGF-β expression and suppresses kidney fibrosis through the autophagic degradation of mature TGF-β [108], which contributes to the occurrence of diabetic diffuse glomerulosclerosis and the excessive deposition of fibrotic materials in DN [109]. The LC3-II/LC3I ratio, Atg5 level, and Atg7 expression in the diabetic kidney with Sirt1 knockdown sharply declined [110], whereas Sirt1-induced autophagy was enhanced in an experimental model of DN [111]. Additionally, other studies have indicated that AMPK downregulation [112] and mTORC1 upregulation [113] are two key players in orchestrating events in autophagy and aging, which are crucial for the onset or progression of DN [114, 115].

Impaired autophagy has been demonstrated in vivo in DN patients that LC3 and P62 accumulation in the kidney of DN patients [116] and DN animal models [117], as well as in vitro [106]. Actually, the antisenescence of autophagy remains controversial. Oxidative stress-induced senescence is linked to autophagy impairment [118]. Mitochondrial dysfunction induced by high glucose is the main cause of oxidative stress and triggers senescence of TECs which can be modulated by mitophagy [119]. It was reported that atg5-deficient podocytes developed a series of aging-related alterations, such as lipofuscin accumulation and damaged mitochondria increase, the load of oxidized proteins, and the occurrence of ubiquitin and p62/SQSTM1-positive protein aggregates [120]. However, another study illustrated that silencing atg-5 reduced the hallmarks of stresses-induced TEC senescence [121]. It was clarified that general autophagy played an antisenescence role, but under stresses, once cells over a certain time point in senescence, autophagy showed prosenescence because of removing stresses that senescent cells must treat with [122]. More interestingly, it was reported that increased lysine63 ubiquitination not the whole level of ubiquitin was related to impaired autophagy and apoptosis of TEC induced by hyperglycemia [116]. So how autophagy in DN influences cell fates remains complicated. For atherosclerosis, defective autophagy promoted senescence and apoptosis in endothelial cells. Defects in autophagic machinery seemed to initiate apoptosis, while the expression of p53 was likely to onset senescence. Anyhow, senescence and apoptosis were two complementary cell fates controlled by autophagy [123]. Nevertheless, in DN, more studies are needed to conduct to elucidate how autophagy promotes cell fates.

5.4. Lysosome and Kidney Aging

Lysosomes are the main catabolic organelles essential for cell homeostasis that are found in all animal cell types except for erythrocytes and play a pivotal role in regulating a variety of processes, such as calcium signaling and nutrient responses to autophagic degradation of intracellular components. Lysosomes have been reported to have important significance in the control of lifespan [124]. Specifically, lysosomal dysfunction induces failure of cellular homeostasis during aging, which reduces the overall degradative capacity of cells and influences cellular and organismal life and death [124, 125]. Cellular senescence is partly determined by the lysosomal function related to mitochondria. Lysosomal dysfunction induces the imbalance of mitochondrial turnover, resulting in the generation of more ROS, which in turn targets lysosomes [126]. In ROS-senescence, mitochondrial dysfunction plays an initiating role, while lysosomal dysfunction is more directly responsible for senescence [118].

It is well established that lysosomal-cathepsins translocation, caused by lysosomal membrane permeabilization (LMP) (Figure 3), induces lysosomal-dependent cell death (LDCD), which has been observed in some age-related diseases, such as Parkinson’s disease [127, 128]. In the study of DN, renal TECs with AGEs stimulation triggered the lysosomal membrane permeabilization, resulting in a decrease of activity of cathepsin B and cathepsin L, lysosomal acidification, and defective degradation of DQ-ovalbumin. However, these effects of AGEs can be blocked by antibodies against AGE-specific receptors or by antioxidants, which indicates that in the condition of DN, oxidative stress may play an important role in lysosomal dysfunction and further lead to tubular cell senescence and apoptosis [106]. Furthermore, urinary LAMP-2 levels are significantly decreased in patients with DN, which correlated with the urinary albumin to creatinine ratio (ACR) and GFR and might lead to the accumulation of autophagic vacuoles [129]. Lysosomal cathepsins are responsible for initiating and executing cell death during aging [130] (specifically in the kidney), and dysregulation of cathepsins B, D, L, and S is shown to be responsible for the onset or progress of kidney diseases [131]. Altered cathepsin D was captured in the tubulointerstitium of renal tissue from patients with DN, and, more precisely, cathepsin D upregulation suppressed the LMP and loss of mitochondrial membrane potential triggered by AGEs, which suggests a protective role in DN [132].

Recent data unveil mTOR activation, nuclear translocation of transcription factor EB (TFEB) inhibition, and the interaction between mTOR and TFEB in glomeruli from db/db mice and podocytes treated with AGEs, which is an irreplaceable factor that involved in the pathogenesis of DN [133]. Previous work has confirmed that TFEB is the master gene in coordinating lysosomal expression and its regulated network [134] and regulates lysosomal biogenesis and cellular clearance [135, 136]. Multiple lines of evidence indicate that mTORC1 resides at the lysosomal surface [135], in response to nutrient-sensing pathways [137], and accelerates cellular and organismal senescence [138, 139]. Hence, in the context of aging and longevity, it will be captivating to eavesdrop on the “cross-talk” between kidney disease and aging through lysosome-based signaling pathways.

6. Main Consequences of Accelerated Kidney Aging in DN

There are two main consequences from the accelerated kidney aging in DN. First, more rapid GFR declines. Kidney aging is featured with the reducing GFR. Due to chronic hyperglycemia, hypertension, and proteinuria, 34.8% of patients have a progressive disease with an annual GFR decline of due to chronic hyperglycemia, hypertension, and proteinuria [140]. Significantly, DN patients with heavy proteinuria experience a rapid renal deterioration with the rate of decline of 46–60 mL/min/1.73 m2/year [141]. Those represent a more accelerated decline compared to normal biological aging at an average rate of 1 mL per year after 30 years old [142]. Second, kidney aging triggers system aging, contributing to the mortality of DN. Patients with DM and CKD have a sharply higher risk for cardiovascular diseases (CVD) compared to diabetic patients with no CKD and CVD, not ESRD seems to be the main cause of death [143]. In Japan, DN has been the main cause of chronic hemodialysis and in populations with chronic hemodialysis, the morbidity of frailty in the DN group was significantly higher than that in the non-DN group [144]. Alarmingly, 32.7% of individuals with DN have frailty significantly increasing the risk of developing ESRD and mortality [145]. A variety of other phenotypes of premature aging still have been observed in patients with CKD, such as the following: vascular calcification, cardiac insufficiency, osteoporosis caused by calcium and phosphorus metabolism disorders, muscle atrophy, and cognitive dysfunction [43, 146, 147]. As a specific CKD, aging-related DN is closely related to systemic aging. A range of factors play a part role in the aging-related decline in renal function, including increased levels of oxidative stress and inflammatory reactions, activation of the RASS, and the stress resistance responses, excessive secretion of angiotensin II, mTOR overactivation, deficiency of Klotho and vitamin D [21, 44]. These factors mentioned above could have a role in impairing the antiaging pathway and may underlie premature aging in DN [96, 148150]. In 852 healthy adults aged 30–98 years, Han et al. reported that declines of naturally aging-related renal function and cardiac diastolic function are not independent processes [151]. In addition, sarcopenia in elderly patients with kidney diseases had a higher prevalence compared with that of younger ones [152], which may provide a better understanding that kidney aging accelerates systemic multiple organ dysfunction.

7. Potential Therapeutic Strategy Targeting Accelerated Kidney Aging in DM

Animal models have shown that diet interventions retard systemic and kidney aging, especially diets with low-AGE contents and enrichment of antioxidants [153]. A 40% adult-onset calorie restriction tended to suspend the age-related structural alterations of kidney-like glomerulosclerosis, interstitial-fibrosis formation, and vascular-wall thickening, which was associated with the decrease of the accumulation of mitochondrial enzyme abnormalities [154]. Short-term caloric restriction was demonstrated to play a protective role against renal senescence via increasing autophagic activity and reducing oxidative stress [155], which may be related to the modulation of AMPK/mTOR signaling [156], attenuating inflammatory process via downregulation of NF-κB [157], as well as the suppression of apoptosis [158]. For humans, some clinical studies have reported the effects of diet restriction for diabetic kidneys. Calorie restriction exhibits renoprotection via amelioration of glomerular hyperfiltration of patients with T2DM with abdominal obesity [159]. With a period of four months of low protein-diet intervention, renal function with a restricted glucose control improved among diabetic patients with macroalbuminuria [160]. However, there is a lack of evidence to show whether there is a beneficial effect of long-term diet restriction for diabetic patients with kidney lesions [161].

Considered a caloric restriction mimetic, resveratrol, a natural polyphenol extracted from grapes and several plants, is characterized as a powerful free-radical scavenger and antioxidant and has been recognized to have an effect on antiaging and life extension. A clinical trial showed that resveratrol might be an effective complementary selection with ARBs to reduce albuminuria in patients with DN [162]. Animal experiments have illustrated that resveratrol restrains the oxidative stress markers in diabetic rats, decreased the expression of renal TGF-β1 and FN [163], which might be associated with the activation of Sirt1 and PGC-1α [164], and increased the expression of Foxo1 [165] and PPARδ [166]. Multiple signaling pathways, including PI3K/Akt, c-Jun N-terminal kinase (JNK)/NF-κB, Akt/NF-κB, and p38 MAPK/TGF-β, have been demonstrated to underlie the renoprotective mechanisms of resveratrol [167] and its antiaging effect in diabetic kidneys [168]. Interestingly, it has been reported that resveratrol has the potential capacity to increase the expression of antiaging proteins such as Klotho and Sirt1 to alleviate the vascular calcification in CKD.

Metformin application remains controversial for DN due to its risk on hyperlactatemia and renal impairment in moderate-to-severe CKD, especially in the elderly [169, 170]. Actually, dosage adjustment of metformin appears to be safe and efficacious for moderate-to-severe CKD, and evidence has shown its potential benefits in lowering the risk of death and cardiovascular event in stage 3 CKD and sustaining calcium-phosphorus homeostasis to prevent vascular calcification [171, 172]. Metformin has shown antiaging benefits in diseases including DM and CKD [173175] and in reducing the all-cause mortality and diseases of aging, including tumors and cardiovascular diseases of diabetics, even compared to nondiabetic [176]. The activation of AMPK plays a vital role in the mechanisms underlying the beneficial effects of metformin for DN. Hyperglycemia gave rise to suppression of phosphorylation and activity of AMPK, leading to multiple pathophysiological changes [177]. Metformin has elucidated the protective effect on podocytes, glomerular mesangial cells, and proximal tubular epithelial cells. In vitro, metformin showed antiapoptosis of podocytes induced by high glucose due to activation of AMPK and inhibition of mTOR signaling [178], and the activation of AMPK seemed to be associated with the activation of P2 receptors via upregulation extracellular ATP concentration [179]. Additionally, metformin adjusted nephrin protein expression [180] and repressed oxidative injury to restore podocytes [181] and also relieved insulin resistance of podocytes through activating Sirt1 and AMPK in diabetic rats [182]. Metformin alleviated inflammation of mesangial cells [183], which was related to upregulated glucagon-like peptide-1 (GLP-1) receptor expression [184]. The Sirt1/Foxo1 signal pathway was focused on demonstrating the antioxidative stress effect of metformin subsequently with the activation of autophagy in diabetic rats and high-glucose-induced mesangial cells [185, 186]. Increasing PGC-1α expression in high-glucose-induced TECs and suppression of AKT and mTOR activation in proteinuria induced TECs, subsequently followed by augmented autophagy and mitochondrial dynamics or ER stress that contributed to the renoprotective effects of metformin in DN [187, 188]. Meanwhile, metformin and rapamycin reversed high-glucose-induced premature senescence of renal cells, as well as induced downregulation of Connexin43 via activation of AMPK and the inhibition of mTOR [189], while the P21 expression was suppressed via modulation of AMPK by metformin-independent repression of mTOR [190].

It is important to note that not only metformin but other antidiabetic agents show emerging renoprotection targeting renal cellular senescence. It has been reported that in patients with type 2 diabetes and kidney disease, compared to a placebo, the inhibitor of (sodium-glucose cotransporter-2) SGLT2, canagliflozin, indeed decreased the relative risk of ESRD, a doubling of the creatinine level or death from renal caused by 34% [191]. This result indicates that SGLT2 inhibitors might be the new hope of the patients with DN after the use of renin-angiotensin system blockers over the past 18 years. The underlying mechanism may be related to its antisenescence of renal cells resulting from the fact that SGLT2 increased the expression of senescent markers in proximal tubules [76] and endothelial cells [192] in DM, indicating that SGLT2 inhibitors might retard renal accelerated aging in DM to preserve kidney function. Other antidiabetic agents reported to protect against accelerated aging are dipeptidyl peptidase 4 (DPP4) inhibition and GLP-1 receptor agonists, which act on the modulation of incretin that protect against age-related diseases including DN [193]. Actually, DPP4 inhibition demonstrated clear antiaging effects.

The lifespan of klotho−/− mice was prolonged, and their body weight was significantly related to greater kidney weight in the intervention of linagliptin [194]. Although no conclusive evidence has demonstrated that DPP4 inhibition improves diabetic kidney lesions, it may control blood glucose and albuminuria as well as be tolerated in patients with DM and CKD, indicating potential renal benefits [195]. It has been reported that rectification of the imbalance between DPP4 and GLP-1 is helpful to vascular aging [196]. Thus, besides DPP4 inhibition, GLP-1 receptor agonists have also shown antiaging potential. GLP-1 receptor agonists showed renoprotection independent of glycemic control, such as inhibition of cellular apoptosis, inflammation, and oxidative injury via the upregulation of Sirt1 [197]. Nevertheless, the renoprotective effect had seemingly acted indirectly on the kidney but was associated with a systemic immunomodulatory effect [198].

PPARγ expresses a low level in kidneys, and it has been shown that its expression and activity reduce during aging and results in the loss of aging-associated function [199]. Pioglitazone presented antiaging via the upregulation of Sirt1 and Klotho, decreased the p53 protein level in aged ApoE-/- mice [200], and alleviated aging-related renal injury via modulation on mitochondrial function [201]. Clinical studies suggested that low-dose pioglitazone was an effective renoprotective method in DN [202, 203]. As a result, pioglitazone showed its potential protection against accelerated senescence in DN.

Considering that oxidative stress plays a major role in the progress of DN and accelerates the kidney aging, chronic antioxidant supplements are eagerly sought after for their long-term benefits. Antioxidants (including vitamin C, vitamin E, and zinc) may protect against early renal damage [204]. High-dose vitamin E supplements in the treatment of DN resulted in a notable decrease in urine protein, which may be partly associated with the alleviation of autophagic stress in TECs [117, 205]. Nicotinamide adenine dinucleotide (NAD) functions as a coenzyme in redox reactions and mediates many biological processes, including metabolism and aging, as well as metabolic diseases like DM [206, 207]. As a hallmark of aging, NADs are related to the inducing of autophagy, repairing DNA and activation of Sirt1 and NADs, which are regulated by AMPK [208]. The age-dependent decrease of NADs happens in many tissues, including kidneys [206]. NAD precursors can delay aging and counteract a broad spectrum of age-related diseases. It has been reported that NAD replenishment contributed to retarding the renal lesion in diabetic rats. However, the precision of NAD+ supplementation is needed due to the regulation of SASP leading to tumor-promoting effects [209]. Actually, a number of studies are focused on antioxidant supplementation in the treatment of DN, but conclusive evidence is still lacking to demonstrate their long-term clinical benefits.

Owing to the fact that fewer senescence cells can even lead to reduced survival in older individuals, senotherapies, such as selective elimination of senescent cells (senolytics) or the disruption of the senescent cells’ secretome (senostatics), are gaining significant attention from researchers to retard the progression of aging-related diseases [210, 211]. So far, dozens of senolytics have been reported, which have been considered adjunctive therapies for aging-related diseases such as tumors [212], idiopathic pulmonary fibrosis [213], Alzheimer’s disease [214], and renal disease [215]. These reports suggest that senolytics may be a beneficial supplementary therapy for DM patients with chronic kidney injuries. A recent clinical study reported that 3 d of oral Dasatinib and Quercetin alleviated adipose tissue senescent cell burden and decreased skin epidermal p16INK4A+ and p21CIP1+ cells and circulating SASP factors in patients with DN, indicating that senolytics relieved senescent cell burden [216]. Hence, it is hypothesized that a similar intervention could be complementary to clinic therapy in the treatment of DN in the future. Actually, the application of senotherapies in aging-related disease remains uncertain [217], including their specific-kidney protection, so more clinical and further studies are needed.

Simultaneously, traditional Chinese medicine (TCM) is another popular option for DN because of its definite curative effect. The renal protection offered by Shenkang injection, a classic compound prescription, has also been demonstrated to retard high glucose-induced senescence of renal tubular cells [218]. Some extracts of herbs have exhibited antiaging properties, such as curcumin [219, 220], a glycoprotein isolated from Fupenzi [221], tea polyphenols [222], the flavonoid 4,4-dimethoxychalcone (DMC) [102], and berberine [223]. These results imply that TCMs appear to have potential advantages to protect renal function against kidney aging in DM in the future. The potential mechanisms of drugs with antiaging properties applied to DN are summarized in Table 2.


DrugsBeneficial effectsMechanismsIn vivoIn vitroRef.

ResveratrolAttenuation of renal fibrosisRegulation of AMPK/NOX4/ROS signalingdb/db mice[255]
ResveratrolRenoprotectionEnhancement of hypoxia-induced autophagy via Sirt1STZ-induced diabetic rats,Hypoxic-condition-induced rat proximal tubular epithelial cells NRK-52e[110]
ResveratrolSuppression of renal inflammation and mesangial cell proliferationModulation on Akt/NF-𝜅B pathwaySTZ-induced diabetic rats;HG-induced rat mesangial cells[256]
ResveratrolRegulating oxidative stress and mitochondrial functionModulation of the Sirt1/FoxO1 signal pathwaySTZ-induced diabetic ratsHG-induced rat mesangial cells[165, 257]
ResveratrolRenoprotectionExtenuating the oxidative stress and downregulation of RAGE expressionSTZ-induced diabetic rats[258]
ResveratrolAmeliorating lipotoxicity, oxidative stress, apoptosis, endothelial dysfunction; glomerular matrix expansion and inflammationActivating the AMPK-Sirt1-PGC-1α axis and PPARα through increases in AdipoR1 and AdipoR2 expressiondb/db miceHG-induced human glomerular endothelial cells and NMS2 mesangial cells[259, 260]
ResveratrolProtection on podocytesActivation of autophagy involved with miR-383-5pdb/db miceHG-induced human podocytes[261]
ResveratrolProtection on mesangial cellsNegative regulation of the p38 MAPK/TGF-β1 pathwaySTZ-induced diabetic ratsHG-induced rat mesangial cells[167]
ResveratrolProtection on podocytesAgainst apoptosis by increasing autophagy via miRNA-18a-5p expressiondb/db miceHG-induced human podocytes[262]
ResveratrolEffect on endoplasmic reticulum stressReducing expressions of 78 kDa glucose-regulated protein (GRP78), protein kinase RNA-like endoplasmic reticulum kinase (PERK), and activating transcription factor 4 (ATF4) and C/EBP-homologous protein (CHOP)STZ induced diabetic rats[263]
ResveratrolProtection on podocytesReducing oxidative damage and apoptosis of podocytes via Sirt1/PGC-1α mitochondrial protectionHG-induced immortalized mouse podocytes[164]
ResveratrolRenoprotection and reducing albuminuriaSuppression of the angiotensin II (Ang II)/angiotensin II type 1 receptor (AT1R) axis and enhancing the angiotensin 1-7 (Ang 1-7)/Mas receptor (MasR) axis; anti-inflammation and oxidative stressAged C57BL/6 mice[30]
ResveratrolRegulation on endothelial dysfunctionModulation of Sirt1 and PPARγdb/db mice[166]
MetforminRestore the insulin responsiveness of podocytesRegulating Sirt1 and AMPK activitiesHG-induced rat podocytes[182]
MetforminExhibiting an anti-apoptotic impact on podocytesActivation of AMPK and inhibition of mTOR signalingHG-induced immortalized human podocytes[178]
MetforminRenoprotective effectIncreasing SOD activity and decreasing malondialdehyde level; decreasing the expression levels of TGF-β1STZ-induced diabetic rats[264]
MetforminImproving diabetic tubulopathyIncreasing in PGC1α activity by modulating mitochondrial dynamics and autophagySTZ-induced diabetic mice,HG-induced human renal proximal tubular epithelial cell line HKC8[188]
MetforminAgainst proteinuria cytotoxicitySuppression of Akt and mTOR activation, inhibition of EMT and apoptosis and augmentation of autophagy and ER defense response through AMPK-independent and AMPK-dependent mechanismsAlbumin-induced rat renal proximal tubular cells[187]
MetforminProtection on podocytesUpregulating the renal tissue nephron expressionSTZ-induced rats[180]
MetforminProtection on podocytesIncreases extracellular ATP concentration, leading to activation of P2 receptors and consequent modulation of the podocytes’ metabolism through AMPK and NAD(P)H oxidaseHG-induced mouse podocytes[179]
MetforminAlleviation of cell senescenceDownregulation of Connexin43 via activation of AMPK and the inhibition of mTORHG-induced primary rat glomerular mesangial cells[189]
MetforminAlleviation of high-glucose-induced oxidative stressRegulating p-p38MAPK protein expressionHG-induced rat glomerular mesangial cells[265]
MetforminAlleviation of inflammationInhibits nuclear factor-κB activation and inflammatory cytokines expression including monocyte chemoattractant protein-1 (MCP-1), intercellular adhesion molecular depend on AMPKHG-induced rat glomerular mesangial cells[183]
MetforminInhibition of apoptosis and inflammatory and fibrotic reactions in tubular cellsReducing ROS generation via suppression of RAGE expression through AMP-activated protein kinase activationAGEs induced human proximal tubular epithelial cells[266]
MetforminRelieving oxidative stress, slowed down abnormal cell proliferationEnhancing autophagy and through Sirt1/FoxO1 pathway via AMPKSTZ-induced diabetic rats;HG-induced rat mesangial cells,[185, 186]
MetforminExerting anti-inflammatoryUpregulating GLP-1R expression via AMPKdb/db miceHG-induced rat mesangial cell line (HBZY-1)[184]
MetforminAttenuating hypoxiaReducing uncoupling protein-2- (UCP2-) mediated mitochondrial proton LEAKSTZ-induced diabetic rats[267]
MetforminAlleviating cell senescenceReducing p21 expression by activating AMPK.Human embryonic kidney (HEK293) cell line[190]
MetforminImproving epithelial-to-mesenchymal transitionInhibiting early growth response- (Egr-) 1; inhibiting MCP-1 expression via BMP and activin membrane-bound inhibitor- (BAMBI-) mediated inhibition of ERK1/2TGF-β1-induced rat renal tubular epithelial cell line (NRK-52E)[268, 269]
GLP-1Protection of podocytesAgainst apoptosis, inhibition reactive oxygen species production and proinflammatory cytokine secretion, through Sirt1 activationHG-induced mouse podocytes[197]
GLP-1R agonist (Exendin-4)Against renal fibrosisInhibiting the transfer of extracellular vesicle miR-192HG-induced renal tubular epithelial cells[270]
GLP-1R agonist (Exendin-4)Inhibiting cell proliferation and fibronectin secretionReversing ERK phosphorylation and enhancing expression of mTOR via AMPKHG-induced rat mesangial cells[271]
GLP-1 analog (liraglutide)Against renal inflammatory and protection on endothelial cellsInhibiting STAT3/JAK2 expression via SIRT1db/db miceAGEs- or HG-induced endothelial cells[272]
GLP-1R analog (liraglutide)Ameliorating early renal injuryIncreasing the expression of FoxO1 mRNA and reducing renal phosphorylation levels of Akt and FoxO1 proteinSTZ-induced diabetic rats[273]
GLP-1R analog (liraglutide)Renoprotective effectInhibiting autophagy and apoptosis dependent on GLP-1RHG-induced human renal tubular epithelial cell line (HK-2)[274]
GLP-1 analog (liraglutide)Against oxidative stress and albuminuriaVia a PKA-mediated inhibition of renal NAD(P)H oxidaseSTZ-induced diabetic ratsHG-induced human mesangial cells[275]
DPP 4 inhibitor (sitagliptin)Attenuation of glomerular lesionsAlleviation of oxidative injurySTZ-induced diabetic rats[276]
SGLT2i (dapagliflozin)Attenuation of renal fibrosisElevating O-GlcNAcylation and tubular hypoxiaSTZ-induced diabetic ratsHG-induced human proximal tubular epithelial cell line (HK-2)[277]
SGLT2i (dapagliflozin)Against inflammation and postponing the progression of renal injuryInhibition of HMGB1-RAGE-NF-κB signaling pathwayHG-induced human proximal tubular epithelial cell line (HK-2)[278]
SGLT2i (canagliflozin)Against renal inflammation, extracellular matrix turnover and fibrosisReduction in TNFR1, IL-6, MMP7 and FN1HG-induced human proximal tubular epithelial cell line (HK-2)[279]
SGLT2i (Ipragliflozin)Improvements in glomerular damageNormalizing the levels of accumulated tricarboxylic acid cycle intermediates and increased oxidative stressdb/db mice[280]
SGLT2i (Empagliflozin)Anti-inflammatory and antifibrotic effectsSuppressing AGE-RAGE axisSTZ-induced diabetic rats[281]
PioglitazoneReprotection in DMDecreasing expression of hypoxia-inducible factor-1a (HIF-1a) and vascular endothelial growth factor (VEGF)STZ-induced diabetic rats[282]
PioglitazoneAmeliorating aging-related renal injuryIncreasing klotho, decreasing oxidative stress, and mitochondrial injury; regulating p66Shc phosphorylation, which integrates many signaling pathways that affect mitochondrial function and longevity, by reducing protein kinase CAging male Sprague-Dawley rats[201]
Dasatinib and quercetinDecreasing human senescent cell burdenAlleviating adipose tissue senescent cell burden, decreasing skin epidermal p16INK4A+ and p21CIP1+ cells and circulating SASP factors in patients with DNHuman tissues[216]

Abbreviations: STZ: streptozotocin; DN: diabetic nephropathy; HG: high glucose; GLP-1: glucagon-like peptide-1; DPP4: dipeptidyl peptidase 4; SGLT2i: sodium-glucose cotransporter-2 inhibitor; AMPK/NOX4/ROS: AMP-activated protein kinase/NADPH oxidase-4/reactive oxygen species; Akt/NF-κB: protein kinase B/nuclear factor kappa-B; FoxO1: forkhead box O 1; PGC-1: peroxisome proliferator-activated receptor- (PPAR-) α coactivador-1; AdipoR: adiponectin receptor protein; MAPK: mitogen-activated protein kinase; TGF-β: transforming growth factor-β: mTOR: mammalian target of rapamycin; SOD: superoxide dismutase; EMT: epithelial-mesenchymal transdifferentiation; RAGE: receptor for advanced glycation end products (AGEs); HMGB1: high mobility group box 1-receptor; ERK: extracellular signal-regulated kinase; STAT3: signal transducer and activator of transcription; JAK2: janus kinase 2; TNFR1: TNF receptor 1; MMP7: matrix metalloproteinase 7; FN1: fibronectin 1.

8. Conclusion

Accelerated senescence of kidneys plays a vital role in DN progression. To delay renal lesions in DM or DN patients, accelerated or premature kidney aging must be delayed. The underlying mechanisms of accelerated kidney aging in DM or DN remain complex and multiple. Hyperglycemia, inflammation, oxidative stress, and hypertension induce renal inherited cellular senescence and the downregulation of antiaging proteins, such as Sirt1 and Klotho, and the inactivation of the lysosome-dependent autophagy pathway.

Antihyperglycemia is the most important factor in the treatment of DM and the prevention of DN. Metformin, pioglitazone, and the inhibitor of SGLT2 have been reported to exhibit antisenescence effects independent of antihyperglycemia. Owing to its certain renoprotection for DN patients, inhibitors of SGLT2 are given priority to consideration besides ACEI/ARBs. Additionally, metformin and pioglitazone should be more considered in the treatment of DM and in the early stage of DN. In addition, for DM or DN patients, antioxidant-rich food and antisenescence-compound-rich food are recommended. However, it should be noted their intake should be considered according to their sugar content. Concurrently, moderate calorie restriction and a level of exercise are encouraged for patients with DM and early DN.

Autophagy is the common downstream of aging-related pathways and is central to DN progression. Unfortunately, the regulation and activity mechanisms of autophagy remain incompletely understood with respect to DN. It has been proved that Sirt1 has been regulating autophagy through the deacetylation of Atg5, Atg7, and Atg8 [224]. Autophagy extended the lifespan of mice knock-out Klotho [225], and Klotho attenuated renal lesions by regulating the autophagy clearance [226]. Based on these studies, we identified a key link between antiaging proteins like Sirt1, Klotho in DN, but further studies are still necessary to illustrate how the antiaging proteins regulate the autophagy and the exact sites for autophagy modulation.

Conflicts of Interest

The authors declare no conflicts of interest.

Authors’ Contributions

YXW, WJL (Wei Jing Liu), JG, and HJZ contributed to the conception, design, and drafting of the manuscript. JG, WTZ, and WJL (Weijiao Lou) contributed to the optimization of the design. CHX and WJH helped optimize the drafting of the manuscript. FZ and XTH helped screen the literature. JG and WJL (Wei Jing Liu) contributed to the revised version. The final version was approved for submission by all authors. Jing Guo and Hui Juan Zheng contributed equally to this work.

Acknowledgments

This study was supported by the National Natural Science Foundation of China (Grant No. 81774298 and 81774278) and the Fundamental Research Funds for the Central Universities (Grant No. 2019-JYB-XS-043), but this research did not receive any public funding from commercial, or not-for-profit, sectors.

References

  1. Federation ID, IDF Diabetes Atlas, Belgium: International Diabetes Federation, Brussels, 9th edition, 2019.
  2. R. K. Hsu and N. R. Powe, “Recent trends in the prevalence of chronic kidney disease: not the same old song,” Current Opinion in Nephrology and Hypertension, vol. 26, no. 3, pp. 187–196, 2017. View at: Publisher Site | Google Scholar
  3. L. Zhang, J. Long, W. Jiang et al., “Trends in chronic kidney disease in China,” The New England Journal of Medicine, vol. 375, no. 9, pp. 905-906, 2016. View at: Publisher Site | Google Scholar
  4. P. Romagnani, G. Remuzzi, R. Glassock et al., “Chronic kidney disease,” Nature Reviews Disease Primers, vol. 3, no. 1, article 17088, 2017. View at: Publisher Site | Google Scholar
  5. D. G. A. Burton and R. G. A. Faragher, “Obesity and type-2 diabetes as inducers of premature cellular senescence and ageing,” Biogerontology, vol. 19, no. 6, pp. 447–459, 2018. View at: Publisher Site | Google Scholar
  6. C. J. Martinez, G. J. Sangros, S. F. Garcia et al., “Chronic renal disease in Spain: prevalence and related factors in persons with diabetes mellitus older than 64 years,” Nefrología, vol. 38, pp. 401–413, 2018. View at: Google Scholar
  7. M. C. Thomas, M. E. Cooper, and P. Zimmet, “Changing epidemiology of type 2 diabetes mellitus and associated chronic kidney disease,” Nature Reviews. Nephrology, vol. 12, no. 2, pp. 73–81, 2016. View at: Publisher Site | Google Scholar
  8. H. J. Anders, T. B. Huber, B. Isermann, and M. Schiffer, “CKD in diabetes: diabetic kidney disease versus nondiabetic kidney disease,” Nature Reviews Nephrology, vol. 14, no. 6, pp. 361–377, 2018. View at: Publisher Site | Google Scholar
  9. R. Schmitt and A. Melk, “Molecular mechanisms of renal aging,” Kidney International, vol. 92, no. 3, pp. 569–579, 2017. View at: Publisher Site | Google Scholar
  10. C. G. Musso and D. G. Oreopoulos, “Aging and physiological changes of the kidneys including changes in glomerular filtration rate,” Nephron. Physiology, vol. 119, Supplement 1, pp. 1–5, 2011. View at: Google Scholar
  11. A. Denic, J. C. Lieske, H. A. Chakkera et al., “The substantial loss of nephrons in healthy human kidneys with aging,” Journal of the American Society of Nephrology, vol. 28, no. 1, pp. 313–320, 2016. View at: Publisher Site | Google Scholar
  12. R. J. Glassock and A. D. Rule, “Aging and the kidneys: anatomy, physiology and consequences for defining chronic kidney disease,” Nephron, vol. 134, no. 1, pp. 25–29, 2016. View at: Publisher Site | Google Scholar
  13. Z.-Y. Duan, G.-Y. Cai, Y.-Z. Chen et al., “Aging promotes progression of IgA nephropathy: a systematic review and meta-analysis,” American Journal of Nephrology, vol. 38, no. 3, pp. 241–252, 2013. View at: Publisher Site | Google Scholar
  14. J. Liu, J.-R. Yang, X.-M. Chen, G.-Y. Cai, L.-R. Lin, and Y.-N. He, “Impact of ER stress-regulated ATF4/p 16 signaling on the premature senescence of renal tubular epithelial cells in diabetic nephropathy,” American Journal of Physiology-Cell Physiology, vol. 308, no. 8, pp. C621–C630, 2015. View at: Publisher Site | Google Scholar
  15. M. C. Thomas, M. Brownlee, K. Susztak et al., “Diabetic kidney disease,” Nature Reviews. Disease Primers, vol. 1, no. 1, p. 15018, 2015. View at: Publisher Site | Google Scholar
  16. A. J. Baldea, “Effect of aging on renal function plus monitoring and support,” Surgical Clinics of North America, vol. 95, no. 1, pp. 71–83, 2015. View at: Publisher Site | Google Scholar
  17. D. Verzola, M. T. Gandolfo, G. Gaetani et al., “Accelerated senescence in the kidneys of patients with type 2 diabetic nephropathy,” American Journal of Physiology-Renal Physiology, vol. 295, no. 5, pp. F1563–F1573, 2008. View at: Publisher Site | Google Scholar
  18. H. Vashistha, L. Marrero, K. Reiss et al., “Aging phenotype (s) in kidneys of diabetic mice are p66ShcA dependent,” American Journal of Physiology. Renal Physiology, vol. 315, no. 6, pp. F1833–F1842, 2018. View at: Publisher Site | Google Scholar
  19. D. Sanajou, A. Ghorbani Haghjo, H. Argani, and S. Aslani, “AGE-RAGE axis blockade in diabetic nephropathy: current status and future directions,” European Journal of Pharmacology, vol. 833, pp. 158–164, 2018. View at: Publisher Site | Google Scholar
  20. K. Matoba, Y. Takeda, Y. Nagai, D. Kawanami, K. Utsunomiya, and R. Nishimura, “Unraveling the role of inflammation in the pathogenesis of diabetic kidney disease,” International Journal of Molecular Sciences, vol. 20, no. 14, p. 3393, 2019. View at: Publisher Site | Google Scholar
  21. D. Choudhury and M. Levi, “Kidney aging--inevitable or preventable?” Nature reviews Nephrology, vol. 7, no. 12, pp. 706–717, 2011. View at: Publisher Site | Google Scholar
  22. N. Nass, B. Bartling, A. Navarrete Santos et al., “Advanced glycation end products, diabetes and ageing,” Zeitschrift für Gerontologie und Geriatrie, vol. 40, no. 5, pp. 349–356, 2007. View at: Publisher Site | Google Scholar
  23. M. Fournet, F. Bonté, and A. Desmoulière, “Glycation damage: a possible hub for major pathophysiological disorders and aging,” Aging and Disease, vol. 9, no. 5, pp. 880–900, 2018. View at: Publisher Site | Google Scholar
  24. R. S. Kazi, R. M. Banarjee, A. B. Deshmukh, G. V. Patil, M. G. Jagadeeshaprasad, and M. J. Kulkarni, “Glycation inhibitors extend yeast chronological lifespan by reducing advanced glycation end products and by back regulation of proteins involved in mitochondrial respiration,” Journal of Proteomics, vol. 156, pp. 104–112, 2017. View at: Publisher Site | Google Scholar
  25. C. Meissner and S. Ritz-Timme, “Molecular pathology and age estimation,” Forensic Science International, vol. 203, no. 1-3, pp. 34–43, 2010. View at: Publisher Site | Google Scholar
  26. S. Ohashi, H. Abe, T. Takahashi et al., “Advanced glycation end products increase collagen-specific chaperone protein in mouse diabetic nephropathy,” The Journal of Biological Chemistry, vol. 279, no. 19, pp. 19816–19823, 2004. View at: Publisher Site | Google Scholar
  27. S. Yamagishi, N. Nakamura, M. Suematsu, K. Kaseda, and T. Matsui, “Advanced glycation end products: a molecular target for vascular complications in diabetes,” Molecular Medicine, vol. 21, Supplement 1, pp. S32–S40, 2015. View at: Publisher Site | Google Scholar
  28. R. Inagi, “RAGE and glyoxalase in kidney disease,” Glycoconjugate Journal, vol. 33, no. 4, pp. 619–626, 2016. View at: Publisher Site | Google Scholar
  29. M. Zain and F. R. Awan, “Renin angiotensin aldosterone system (RAAS): its biology and drug targets for treating diabetic nephropathy,” Pakistan Journal of Pharmaceutical Sciences, vol. 27, no. 5, pp. 1379–1391, 2014. View at: Google Scholar
  30. I.-A. Jang, E. Kim, J. Lim et al., “Effects of resveratrol on the renin-angiotensin system in the aging kidney,” Nutrients, vol. 10, no. 11, p. 1741, 2018. View at: Publisher Site | Google Scholar
  31. H. E. Yoon and B. S. Choi, “The renin-angiotensin system and aging in the kidney,” The Korean Journal of Internal Medicine, vol. 29, no. 3, pp. 291–295, 2014. View at: Publisher Site | Google Scholar
  32. J. M. Garagliano, A. Katsurada, K. Miyata et al., “Advanced glycation end products stimulate angiotensinogen production in renal proximal tubular cells,” The American Journal of the Medical Sciences, vol. 357, no. 1, pp. 57–66, 2019. View at: Publisher Site | Google Scholar
  33. M. K. Sagoo and L. Gnudi, “Diabetic nephropathy: is there a role for oxidative stress?” Free Radical Biology and Medicine, vol. 116, pp. 50–63, 2018. View at: Publisher Site | Google Scholar
  34. S. I. Liochev, “Reactive oxygen species and the free radical theory of aging,” Free Radical Biology and Medicine, vol. 60, pp. 1–4, 2013. View at: Publisher Site | Google Scholar
  35. F. Hu, M. Xue, Y. Li et al., “Early growth response 1 (Egr1) is a transcriptional activator of NOX4 in oxidative stress of diabetic kidney disease,” Journal of Diabetes Research, vol. 2018, Article ID 3405695, 10 pages, 2018. View at: Publisher Site | Google Scholar
  36. X. Chen and M. Fang, “Oxidative stress mediated mitochondrial damage plays roles in pathogenesis of diabetic nephropathy rat,” European Review for Medical and Pharmacological Sciences, vol. 22, pp. 5248–5254, 2018. View at: Google Scholar
  37. Y. Zhang, J. Feng, Q. Wang et al., “Hyperglycaemia stress-induced renal injury is caused by extensive mitochondrial fragmentation, attenuated MKP1 signalling, and activated JNK-CaMKII-Fis1 biological axis,” Cellular Physiology and Biochemistry, vol. 51, no. 4, pp. 1778–1798, 2018. View at: Publisher Site | Google Scholar
  38. T. Takahashi and R. C. Harris, “Role of endothelial nitric oxide synthase in diabetic nephropathy: lessons from diabetic eNOS knockout mice,” Journal of Diabetes Research, vol. 2014, Article ID 590541, 17 pages, 2014. View at: Publisher Site | Google Scholar
  39. H. B. Lee, “Reactive oxygen species-regulated signaling pathways in diabetic nephropathy,” Journal of the American Society of Nephrology, vol. 14, no. 90003, pp. 241S–2245, 2003. View at: Publisher Site | Google Scholar
  40. R. Lindblom, G. Higgins, M. Coughlan, and J. B. de Haan, “Targeting mitochondria and reactive oxygen species-driven pathogenesis in diabetic nephropathy,” The Review of Diabetic Studies, vol. 12, no. 1-2, pp. 134–156, 2015. View at: Publisher Site | Google Scholar
  41. Q. Lu, W. W. Wang, M. Z. Zhang et al., “ROS induces epithelial-mesenchymal transition via the TGF-β1/PI3K/Akt/mTOR pathway in diabetic nephropathy,” Experimental and Therapeutic Medicine, vol. 17, no. 1, pp. 835–846, 2019. View at: Publisher Site | Google Scholar
  42. Y. S. Cheng, J. Chao, C. Chen, L. L. Lv, Y. C. Han, and B. C. Liu, “The PKCβ-p66shc-NADPH oxidase pathway plays a crucial role in diabetic nephropathy,” The Journal of Pharmacy and Pharmacology, vol. 71, no. 3, pp. 338–347, 2019. View at: Publisher Site | Google Scholar
  43. J. P. Kooman, P. Kotanko, A. M. W. J. Schols, P. G. Shiels, and P. Stenvinkel, “Chronic kidney disease and premature ageing,” Nature Reviews Nephrology, vol. 10, no. 12, pp. 732–742, 2014. View at: Publisher Site | Google Scholar
  44. P. Stenvinkel and T. E. Larsson, “Chronic kidney disease: a clinical model of premature aging,” American Journal of Kidney Diseases, vol. 62, no. 2, pp. 339–351, 2013. View at: Publisher Site | Google Scholar
  45. J. A. Moreno, C. Gomez-Guerrero, S. Mas et al., “Targeting inflammation in diabetic nephropathy: a tale of hope,” Expert Opinion on Investigational Drugs, vol. 27, no. 11, pp. 917–930, 2018. View at: Publisher Site | Google Scholar
  46. Z. Rahimi, “The role of renin angiotensin aldosterone system genes in diabetic nephropathy,” Canadian Journal of Diabetes, vol. 40, no. 2, pp. 178–183, 2016. View at: Publisher Site | Google Scholar
  47. E. A. Lee, J. Y. Seo, Z. Jiang et al., “Reactive oxygen species mediate high glucose-induced plasminogen activator inhibitor-1 up-regulation in mesangial cells and in diabetic kidney,” Kidney International, vol. 67, no. 5, pp. 1762–1771, 2005. View at: Publisher Site | Google Scholar
  48. R. C. Campbell, P. Ruggenenti, and G. Remuzzi, “Proteinuria in diabetic nephropathy: treatment and evolution,” Current Diabetes Reports, vol. 3, no. 6, pp. 497–504, 2003. View at: Publisher Site | Google Scholar
  49. E. D. O’Sullivan, J. Hughes, and D. A. Ferenbach, “Renal aging: causes and consequences,” Journal of the American Society of Nephrology, vol. 28, no. 2, pp. 407–420, 2017. View at: Publisher Site | Google Scholar
  50. P. G. Shiels, D. McGuinness, M. Eriksson, J. P. Kooman, and P. Stenvinkel, “The role of epigenetics in renal ageing,” Nature Reviews Nephrology, vol. 13, no. 8, pp. 471–482, 2017. View at: Publisher Site | Google Scholar
  51. F. A. Valentijn, L. L. Falke, T. Q. Nguyen, and R. Goldschmeding, “Cellular senescence in the aging and diseased kidney,” Journal of Cell Communication and Signaling, vol. 12, no. 1, pp. 69–82, 2018. View at: Publisher Site | Google Scholar
  52. R. Schmitt, N. Susnik, and A. Melk, “Molecular aspects of renal senescence,” Current Opinion in Organ Transplantation, vol. 20, no. 4, pp. 412–416, 2015. View at: Publisher Site | Google Scholar
  53. H. Yang and A. B. Fogo, “Cell senescence in the aging kidney,” Journal of the American Society of Nephrology, vol. 21, no. 9, pp. 1436–1439, 2010. View at: Publisher Site | Google Scholar
  54. M.-H. Docherty, E. D. O’Sullivan, J. V. Bonventre, and D. A. Ferenbach, “Cellular senescence in the kidney,” Journal of the American Society of Nephrology, vol. 30, no. 5, pp. 726–736, 2019. View at: Publisher Site | Google Scholar
  55. J. Satriano, H. Mansoury, A. Deng et al., “Transition of kidney tubule cells to a senescent phenotype in early experimental diabetes,” American Journal of Physiology-Cell Physiology, vol. 299, no. 2, pp. C374–C380, 2010. View at: Publisher Site | Google Scholar
  56. D. J. Baker, B. G. Childs, M. Durik et al., “Naturally occurring p16Ink4a-positive cells shorten healthy lifespan,” Nature, vol. 530, no. 7589, pp. 184–189, 2016. View at: Publisher Site | Google Scholar
  57. D. J. Baker, T. Wijshake, T. Tchkonia et al., “Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders,” Nature, vol. 479, no. 7372, pp. 232–236, 2011. View at: Publisher Site | Google Scholar
  58. A. D. Hudgins, C. Tazearslan, A. Tare, Y. Zhu, D. Huffman, and Y. Suh, “Age- and tissue-specific expression of senescence biomarkers in mice,” Frontiers in Genetics, vol. 9, 2018. View at: Publisher Site | Google Scholar
  59. K. Kitada, D. Nakano, H. Ohsaki et al., “Hyperglycemia causes cellular senescence via a SGLT2- and p21-dependent pathway in proximal tubules in the early stage of diabetic nephropathy,” Journal of Diabetes and its Complications, vol. 28, no. 5, pp. 604–611, 2014. View at: Publisher Site | Google Scholar
  60. Q. Guo, X. Li, H. Han et al., “Histone lysine methylation in TGF-β1 mediated p21 gene expression in rat mesangial cells,” BioMed Research International, vol. 2016, Article ID 6927234, 9 pages, 2016. View at: Publisher Site | Google Scholar
  61. T. Yamada, H. Ishihara, A. Tamura et al., “WFS1-deficiency increases endoplasmic reticulum stress, impairs cell cycle progression and triggers the apoptotic pathway specifically in pancreatic beta-cells,” Human Molecular Genetics, vol. 15, no. 10, pp. 1600–1609, 2006. View at: Publisher Site | Google Scholar
  62. J. Liu, K. Huang, G.-Y. Cai et al., “Receptor for advanced glycation end-products promotes premature senescence of proximal tubular epithelial cells via activation of endoplasmic reticulum stress-dependent p21 signaling,” Cellular Signalling, vol. 26, no. 1, pp. 110–121, 2014. View at: Publisher Site | Google Scholar
  63. C. Ruster, T. Bondeva, S. Franke, M. Forster, and G. Wolf, “Advanced glycation end-products induce cell cycle arrest and hypertrophy in podocytes,” Nephrology Dialysis Transplantation, vol. 23, no. 7, pp. 2179–2191, 2008. View at: Publisher Site | Google Scholar
  64. G. Wolf, A. Schanze, R. A. K. Stahl, S. J. Shankland, and K. Amann, “p27Kip1 knockout mice are protected from diabetic nephropathy: evidence for p27Kip1 haplotype insufficiency1,” Kidney International, vol. 68, no. 4, pp. 1583–1589, 2005. View at: Publisher Site | Google Scholar
  65. M. Awazu, “The lack of cyclin kinase inhibitor p27Kip1 ameliorates progression of diabetic nephropathy,” Journal of the American Society of Nephrology, vol. 14, no. 3, pp. 699–708, 2003. View at: Publisher Site | Google Scholar
  66. S. Lopes-Paciencia, E. Saint-Germain, M. C. Rowell, A. F. Ruiz, P. Kalegari, and G. Ferbeyre, “The senescence-associated secretory phenotype and its regulation,” Cytokine, vol. 117, pp. 15–22, 2019. View at: Publisher Site | Google Scholar
  67. W.-J. Wang, G.-Y. Cai, and X.-M. Chen, “Cellular senescence, senescence-associated secretory phenotype, and chronic kidney disease,” Oncotarget, vol. 8, article 64520, 2017. View at: Google Scholar
  68. A. Melk, V. Ramassar, L. M. Helms et al., “Telomere shortening in kidneys with age,” Journal of the American Society of Nephrology, vol. 11, pp. 444–453, 2000. View at: Google Scholar
  69. O. I. Ameh, I. G. Okpechi, C. Dandara, and A. P. Kengne, “Association between telomere length, chronic kidney disease, and renal traits: a systematic review,” OMICS, vol. 21, no. 3, pp. 143–155, 2017. View at: Publisher Site | Google Scholar
  70. C. D-w, J. C-m, C. Wan et al., “Upregulation of MiR-126 delays the senescence of human glomerular mesangial cells induced by high glucose via telomere-p 53-p 21-Rb signaling pathway,” Current Medical Science, vol. 38, pp. 758–764, 2018. View at: Google Scholar
  71. P. Y. Chuang, W. Cai, X. Li et al., “Reduction in podocyte SIRT1 accelerates kidney injury in aging mice,” American Journal of Physiology-Renal Physiology, vol. 313, no. 3, pp. F621–F628, 2017. View at: Publisher Site | Google Scholar
  72. L. Zhou, D.-y. Xu, W.-g. Sha et al., “High glucose induces renal tubular epithelial injury via Sirt1/NF-kappaB/microR-29/Keap1 signal pathway,” Journal of Translational Medicine, vol. 13, no. 1, p. 352, 2015. View at: Publisher Site | Google Scholar
  73. S. Kume, M. Kitada, K. Kanasaki, H. Maegawa, and D. Koya, “Anti-aging molecule, Sirt 1: a novel therapeutic target for diabetic nephropathy,” Archives of Pharmacal Research, vol. 36, no. 2, pp. 230–236, 2013. View at: Publisher Site | Google Scholar
  74. S. Kume, T. Uzu, K. Horiike et al., “Calorie restriction enhances cell adaptation to hypoxia through Sirt1-dependent mitochondrial autophagy in mouse aged kidney,” Journal of Clinical Investigation, vol. 120, no. 4, pp. 1043–1055, 2010. View at: Publisher Site | Google Scholar
  75. M. Waldman, K. Cohen, D. Yadin et al., “Regulation of diabetic cardiomyopathy by caloric restriction is mediated by intracellular signaling pathways involving ‘SIRT1 and PGC-1α’,” Cardiovascular Diabetology, vol. 17, no. 1, p. 111, 2018. View at: Publisher Site | Google Scholar
  76. M. Kitada, A. Takeda, T. Nagai, H. Ito, K. Kanasaki, and D. Koya, “Dietary restriction ameliorates diabetic nephropathy through anti-inflammatory effects and regulation of the autophagy via restoration of Sirt1 in diabetic Wistar fatty (fa/fa) rats: a model of type 2 diabetes,” Experimental Diabetes Research, vol. 2011, Article ID 908185, 11 pages, 2011. View at: Publisher Site | Google Scholar
  77. K. Huang, J. Huang, X. Xie et al., “Sirt1 resists advanced glycation end products-induced expressions of fibronectin and TGF- β 1 by activating the Nrf2/ARE pathway in glomerular mesangial cells,” Free Radical Biology and Medicine, vol. 65, pp. 528–540, 2013. View at: Publisher Site | Google Scholar
  78. M. Xue, Y. Li, F. Hu et al., “High glucose up-regulates microRNA-34a-5p to aggravate fibrosis by targeting SIRT1 in HK-2 cells,” Biochemical and Biophysical Research Communications, vol. 498, no. 1, pp. 38–44, 2018. View at: Publisher Site | Google Scholar
  79. B. L. Tang, “Sirt 1 and the mitochondria,” Molecules and Cells, vol. 39, pp. 87–95, 2016. View at: Google Scholar
  80. K. Huang, X. Gao, and W. Wei, “The crosstalk between Sirt1 and Keap1/Nrf2/ARE anti-oxidative pathway forms a positive feedback loop to inhibit FN and TGF-β1 expressions in rat glomerular mesangial cells,” Experimental Cell Research, vol. 361, no. 1, pp. 63–72, 2017. View at: Publisher Site | Google Scholar
  81. L. Zhang, Z. Chen, W. Gong et al., “Paeonol ameliorates diabetic renal fibrosis through promoting the activation of the Nrf 2/ARE pathway via up-regulating Sirt 1,” Frontiers in Pharmacology, vol. 9, p. 521, 2018. View at: Google Scholar
  82. Q. Zhang, Q. Deng, J. Zhang et al., “Activation of the Nrf2-ARE pathway ameliorates hyperglycemia-mediated mitochondrial dysfunction in podocytes partly through Sirt1,” Cellular Physiology and Biochemistry, vol. 48, no. 1, pp. 1–15, 2018. View at: Publisher Site | Google Scholar
  83. M. Sopjani, M. Rinnerthaler, J. Kruja, and M. Dermaku-Sopjani, “Intracellular signaling of the aging suppressor protein klotho,” Current Molecular Medicine, vol. 15, no. 1, pp. 27–37, 2015. View at: Publisher Site | Google Scholar
  84. M. Dërmaku-Sopjani, S. Kolgeci, S. Abazi, and M. Sopjani, “Significance of the anti-aging protein klotho,” Molecular Membrane Biology, vol. 30, no. 8, pp. 369–385, 2013. View at: Publisher Site | Google Scholar
  85. J.-H. Kim, K.-H. Hwang, K.-S. Park, I. D. Kong, and S.-K. Cha, “Biological role of anti-aging protein klotho,” Journal of Lifestyle Medicine, vol. 5, no. 1, pp. 1–6, 2015. View at: Publisher Site | Google Scholar
  86. Y. Xu and Z. Sun, “Molecular basis of klotho: from gene to function in aging,” Endocrine Reviews, vol. 36, no. 2, pp. 174–193, 2015. View at: Publisher Site | Google Scholar
  87. K. N. T. T. Osamu Asai, “Decreased renal a-klotho expression in early diabetic nephropathy in humans and mice and its possible role in urinary calcium excretion,” International Society of Nephrology, vol. 81, pp. 539–547, 2012. View at: Google Scholar
  88. A. Inci, F. Sari, M. Coban et al., “Soluble klotho and fibroblast growth factor 23 levels in diabetic nephropathy with different stages of albuminuria,” Journal of Investigative Medicine, vol. 64, no. 6, pp. 1128–1133, 2016. View at: Publisher Site | Google Scholar
  89. S. S. Kim, S. H. Song, I. J. Kim et al., “Decreased plasma α-klotho predict progression of nephropathy with type 2 diabetic patients,” Journal of Diabetes and its Complications, vol. 30, no. 5, pp. 887–892, 2016. View at: Publisher Site | Google Scholar
  90. C. Wu, Q. Wang, C. Lv et al., “The changes of serum sKlotho and NGAL levels and their correlation in type 2 diabetes mellitus patients with different stages of urinary albumin,” Diabetes Research and Clinical Practice, vol. 106, no. 2, pp. 343–350, 2014. View at: Publisher Site | Google Scholar
  91. J.-S. Huang, C.-T. Chuang, M.-H. Liu, S.-H. Lin, J.-Y. Guh, and L.-Y. Chuang, “Klotho attenuates high glucose-induced fibronectin and cell hypertrophy via the ERK1/2-p38 kinase signaling pathway in renal interstitial fibroblasts,” Molecular and Cellular Endocrinology, vol. 390, no. 1-2, pp. 45–53, 2014. View at: Publisher Site | Google Scholar
  92. H. Kadoya, M. Satoh, Y. Haruna, T. Sasaki, and N. Kashihara, “Klotho attenuates renal hypertrophy and glomerular injury in Ins2Akita diabetic mice,” Clinical and Experimental Nephrology, vol. 20, no. 5, pp. 671–678, 2016. View at: Publisher Site | Google Scholar
  93. Y. Li, F. Hu, M. Xue et al., “Klotho down-regulates Egr-1 by inhibiting TGF-β1/Smad3 signaling in high glucose treated human mesangial cells,” Biochemical and Biophysical Research Communications, vol. 487, no. 2, pp. 216–222, 2017. View at: Publisher Site | Google Scholar
  94. Y. Zhao, S. Banerjee, N. Dey et al., “Klotho depletion contributes to increased inflammation in kidney of the db/db mouse model of diabetes via RelA (serine)536 phosphorylation,” Diabetes, vol. 60, pp. 1908–1916, 2011. View at: Google Scholar
  95. A. Inci, R. Olmaz, F. Sar, M. Coban, H. Y. Ellidag, and K. M. Sar, “Increased oxidative stress in diabetic nephropathy and its relationship with soluble klotho levels,” Hippokratia, vol. 20, p. 198, 2016. View at: Google Scholar
  96. Y. N. Liu, J. Zhou, T. Li et al., “Sulodexide protects renal tubular epithelial cells from oxidative stress-induced injury via upregulating klotho expression at an early stage of diabetic kidney disease,” Journal of Diabetes Research, vol. 2017, Article ID 4989847, 10 pages, 2017. View at: Publisher Site | Google Scholar
  97. H. Nagasu, M. Satoh, A. Kuwabara et al., “Overexpression of klotho protein modulates uninephrectomy-induced compensatory renal hypertrophy by suppressing IGF-I signals,” Biochemical and Biophysical Research Communications, vol. 407, no. 1, pp. 39–43, 2011. View at: Publisher Site | Google Scholar
  98. N. Mizushima, “Autophagy: process and function,” Genes & Development, vol. 21, no. 22, pp. 2861–2873, 2007. View at: Publisher Site | Google Scholar
  99. E. Lionaki, M. Markaki, and N. Tavernarakis, “Autophagy and ageing: insights from invertebrate model organisms,” Ageing Research Reviews, vol. 12, no. 1, pp. 413–428, 2013. View at: Publisher Site | Google Scholar
  100. D. C. Rubinsztein, G. Marino, and G. Kroemer, “Autophagy and aging,” Cell, vol. 146, no. 5, pp. 682–695, 2011. View at: Publisher Site | Google Scholar
  101. S. Nakamura and T. Yoshimori, “Autophagy and longevity,” Molecules and Cells, vol. 41, no. 1, pp. 65–72, 2018. View at: Publisher Site | Google Scholar
  102. D. Carmona-Gutierrez, A. Zimmermann, K. Kainz et al., “The flavonoid 4,4-dimethoxychalcone promotes autophagy-dependent longevity across species,” Nature Communications, vol. 10, no. 1, p. 651, 2019. View at: Publisher Site | Google Scholar
  103. M. Naguib and L. A. Rashed, “Serum level of the autophagy biomarker Beclin-1 in patients with diabetic kidney disease,” Diabetes Research and Clinical Practice, vol. 143, pp. 56–61, 2018. View at: Publisher Site | Google Scholar
  104. W. J. Liu, W. F. Huang, L. Ye et al., “The activity and role of autophagy in the pathogenesis of diabetic nephropathy,” European Review for Medical and Pharmacological Sciences, vol. 22, no. 10, pp. 3182–3189, 2018. View at: Publisher Site | Google Scholar
  105. W. J. Liu, M.-N. Luo, J. Tan et al., “Autophagy activation reduces renal tubular injury induced by urinary proteins,” Autophagy, vol. 10, pp. 243–256, 2013. View at: Google Scholar
  106. W. J. Liu, T. T. Shen, R. H. Chen et al., “Autophagy-lysosome pathway in renal tubular epithelial cells is disrupted by advanced glycation end products in diabetic nephropathy,” Journal of Biological Chemistry, vol. 290, no. 33, pp. 20499–20510, 2015. View at: Publisher Site | Google Scholar
  107. J. Zhang, X. Xiang, S. Shu et al., “Advanced oxidation protein products inhibit the autophagy of renal tubular epithelial cells,” Experimental and Therapeutic Medicine, vol. 15, pp. 3908–3916, 2018. View at: Google Scholar
  108. Y. Ding, S. Kim, S. Y. Lee, J. K. Koo, Z. Wang, and M. E. Choi, “Autophagy regulates TGF-β expression and suppresses kidney fibrosis induced by unilateral ureteral obstruction,” Journal of the American Society of Nephrology, vol. 25, no. 12, pp. 2835–2846, 2014. View at: Publisher Site | Google Scholar
  109. F. Liu, H. Y. Chen, X. R. Huang et al., “C-reactive protein promotes diabetic kidney disease in a mouse model of type 1 diabetes,” Diabetologia, vol. 54, no. 10, pp. 2713–2723, 2011. View at: Publisher Site | Google Scholar
  110. L. Ma, R. Fu, Z. Duan et al., “Sirt1 is essential for resveratrol enhancement of hypoxia-induced autophagy in the type 2 diabetic nephropathy rat,” Pathology, Research and Practice, vol. 212, no. 4, pp. 310–318, 2016. View at: Publisher Site | Google Scholar
  111. X. Wang, Y. Gao, N. Tian et al., “Astragaloside IV represses high glucose-induced mesangial cells activation by enhancing autophagy via SIRT1 deacetylation of NF-kappaB p 65 subunit,” Drug Design, Development and Therapy, vol. 12, pp. 2971–2980, 2018. View at: Google Scholar
  112. F. Yao, M. Zhang, and L. Chen, “5'-monophosphate-activated protein kinase (AMPK) improves autophagic activity in diabetes and diabetic complications,” Acta Pharmaceutica Sinica B, vol. 6, no. 1, pp. 20–25, 2016. View at: Publisher Site | Google Scholar
  113. Y. Liu, J. Zhang, Y. Wang, and X. Zeng, “Apelin involved in progression of diabetic nephropathy by inhibiting autophagy in podocytes,” Cell Death and Disease, vol. 8, no. 8, article e3006, 2017. View at: Publisher Site | Google Scholar
  114. A. Salminen and K. Kaarniranta, “AMP-activated protein kinase (AMPK) controls the aging process via an integrated signaling network,” Ageing Research Reviews, vol. 11, no. 2, pp. 230–241, 2012. View at: Publisher Site | Google Scholar
  115. H. Walters and L. Cox, “mTORC inhibitors as broad-spectrum therapeutics for age-related diseases,” International Journal of Molecular Sciences, vol. 19, article E2325, 2018. View at: Google Scholar
  116. P. Pontrelli, A. Oranger, M. Barozzino et al., “Deregulation of autophagy under hyperglycemic conditions is dependent on increased lysine 63 ubiquitination: a candidate mechanism in the progression of diabetic nephropathy,” Journal of Molecular Medicine (Berlin, Germany), vol. 96, no. 7, pp. 645–659, 2018. View at: Publisher Site | Google Scholar
  117. Y. Zhao, W. Zhang, Q. Jia et al., “High dose vitamin E attenuates diabetic nephropathy via alleviation of autophagic stress,” Frontiers in Physiology, vol. 9, 2019. View at: Publisher Site | Google Scholar
  118. H. Tai, Z. Wang, H. Gong et al., “Autophagy impairment with lysosomal and mitochondrial dysfunction is an important characteristic of oxidative stress-induced senescence,” Autophagy, vol. 13, pp. 99–113, 2016. View at: Google Scholar
  119. K. Chen, H. Dai, J. Yuan et al., “Optineurin-mediated mitophagy protects renal tubular epithelial cells against accelerated senescence in diabetic nephropathy,” Cell Death & Disease, vol. 9, no. 2, p. 105, 2018. View at: Publisher Site | Google Scholar
  120. M. Jiang, K. Liu, J. Luo, and Z. Dong, “Autophagy is a renoprotective mechanism during in vitro hypoxia and in vivo ischemia-reperfusion injury,” The American Journal of Pathology, vol. 176, no. 3, pp. 1181–1192, 2010. View at: Publisher Site | Google Scholar
  121. A. Baisantry, S. Bhayana, C. Wrede et al., “The impact of autophagy on the development of senescence in primary tubular epithelial cells,” Cell Cycle, vol. 15, no. 21, pp. 2973–2979, 2016. View at: Publisher Site | Google Scholar
  122. Y. Kwon, J. W. Kim, J. A. Jeoung, M. S. Kim, and C. Kang, “Autophagy is pro-senescence when seen in close-up, but anti-senescence in long-shot,” Molecules and Cells, vol. 40, no. 9, pp. 607–612, 2017. View at: Publisher Site | Google Scholar
  123. M. O. J. Grootaert, L. Roth, D. M. Schrijvers, G. R. Y. De Meyer, and W. Martinet, “Defective autophagy in atherosclerosis: to die or to senesce?” Oxidative Medicine and Cellular Longevity, vol. 2018, Article ID 7687083, 12 pages, 2018. View at: Publisher Site | Google Scholar
  124. D. Carmona-Gutierrez, A. L. Hughes, F. Madeo, and C. Ruckenstuhl, “The crucial impact of lysosomes in aging and longevity,” Ageing Research Reviews, vol. 32, pp. 2–12, 2016. View at: Publisher Site | Google Scholar
  125. D. S. Leeman, K. Hebestreit, T. Ruetz et al., “Lysosome activation clears aggregates and enhances quiescent neural stem cell activation during aging,” Science, vol. 359, no. 6381, pp. 1277–1283, 2018. View at: Publisher Site | Google Scholar
  126. J. T. Park, Y.-S. Lee, K. A. Cho, and S. C. Park, “Adjustment of the lysosomal-mitochondrial axis for control of cellular senescence,” Ageing Research Reviews, vol. 47, pp. 176–182, 2018. View at: Publisher Site | Google Scholar
  127. A. Serrano-Puebla and P. Boya, “Lysosomal membrane permeabilization in cell death: new evidence and implications for health and disease,” Annals of the New York Academy of Sciences, vol. 1371, no. 1, pp. 30–44, 2016. View at: Publisher Site | Google Scholar
  128. F. Wang, R. Gomez-Sintes, and P. Boya, “Lysosomal membrane permeabilization and cell death,” Traffic, vol. 19, no. 12, pp. 918–931, 2018. View at: Publisher Site | Google Scholar
  129. Y. Kaburagi, E. Takahashi, H. Kajio et al., “Urinary afamin levels are associated with the progression of diabetic nephropathy,” Diabetes Research and Clinical Practice, vol. 147, pp. 37–46, 2019. View at: Publisher Site | Google Scholar
  130. V. Stoka, V. Turk, and B. Turk, “Lysosomal cathepsins and their regulation in aging and neurodegeneration,” Ageing Research Reviews, vol. 32, pp. 22–37, 2016. View at: Publisher Site | Google Scholar
  131. P. Cocchiaro, V. De Pasquale, R. Della Morte et al., “The multifaceted role of the lysosomal protease cathepsins in kidney disease,” Frontiers in Cell and Developmental Biology, vol. 5, p. 114, 2017. View at: Publisher Site | Google Scholar
  132. F. Du, T. Wang, S. Li et al., “Cathepsin D protects renal tubular cells from damage induced by high glucose independent of its enzymatic activity,” American Journal of Translational Research, vol. 9, no. 12, pp. 5528–5537, 2017. View at: Google Scholar
  133. X. Zhao, Y. Chen, X. Tan et al., “Advanced glycation end-products suppress autophagic flux in podocytes by activating mammalian target of rapamycin and inhibiting nuclear translocation of transcription factor EB,” The Journal of Pathology, vol. 245, no. 2, pp. 235–248, 2018. View at: Publisher Site | Google Scholar
  134. M. Palmieri, S. Impey, H. Kang et al., “Characterization of the CLEAR network reveals an integrated control of cellular clearance pathways,” Human Molecular Genetics, vol. 20, no. 19, pp. 3852–3866, 2011. View at: Publisher Site | Google Scholar
  135. Y. Sancak, L. Bar-Peled, R. Zoncu, A. L. Markhard, S. Nada, and D. M. Sabatini, “Ragulator-rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids,” Cell, vol. 141, no. 2, pp. 290–303, 2010. View at: Publisher Site | Google Scholar
  136. M. Sardiello, “Transcription factor EB: from master coordinator of lysosomal pathways to candidate therapeutic target in degenerative storage diseases,” Annals of the New York Academy of Sciences, vol. 1371, no. 1, pp. 3–14, 2016. View at: Publisher Site | Google Scholar
  137. C. Demetriades, N. Doumpas, and A. A. Teleman, “Regulation of TORC1 in response to amino acid starvation via lysosomal recruitment of TSC2,” Cell, vol. 156, no. 4, pp. 786–799, 2014. View at: Publisher Site | Google Scholar
  138. H. Antikainen, M. Driscoll, G. Haspel, and R. Dobrowolski, “TOR-mediated regulation of metabolism in aging,” Aging Cell, vol. 16, no. 6, pp. 1219–1233, 2017. View at: Publisher Site | Google Scholar
  139. Y. Wei, Y.-J. Zhang, and Y. Cai, “Growth or longevity: the TOR’s decision on lifespan regulation,” Biogerontology, vol. 14, no. 4, pp. 353–363, 2013. View at: Publisher Site | Google Scholar
  140. N. Altemtam, J. Russell, and M. El Nahas, “A study of the natural history of diabetic kidney disease (DKD),” Nephrology Dialysis Transplantation, vol. 27, no. 5, pp. 1847–1854, 2012. View at: Publisher Site | Google Scholar
  141. C. T. S. Lim, N. Z. Nordin, N. Z. Fadhlina et al., “Rapid decline of renal function in patients with type 2 diabetes with heavy proteinuria: a report of three cases,” BMC Nephrology, vol. 20, no. 1, p. 22, 2019. View at: Publisher Site | Google Scholar
  142. X. J. Zhou, D. Rakheja, X. Yu, R. Saxena, N. D. Vaziri, and F. G. Silva, “The aging kidney,” Kidney International, vol. 74, no. 6, pp. 710–720, 2008. View at: Publisher Site | Google Scholar
  143. M. Maqbool, M. E. Cooper, and K. A. M. Jandeleit-Dahm, “Cardiovascular disease and diabetic kidney disease,” Seminars in Nephrology, vol. 38, no. 3, pp. 217–232, 2018. View at: Publisher Site | Google Scholar
  144. Y. Kakio, H. A. Uchida, H. Takeuchi et al., “Diabetic nephropathy is associated with frailty in patients with chronic hemodialysis,” Geriatrics & Gerontology International, vol. 18, no. 12, pp. 1597–1602, 2018. View at: Publisher Site | Google Scholar
  145. K.-L. Chien, D.-C. Chan, J.-W. Huang, J. Wang, and C.-T. Chao, “Frailty predicts an increased risk of end-stage renal disease with risk competition by mortality among 165, 461 diabetic kidney disease patients,” Aging and Disease, vol. 10, 2019. View at: Google Scholar
  146. A. Covic, M. Vervloet, Z. A. Massy et al., “Bone and mineral disorders in chronic kidney disease: implications for cardiovascular health and ageing in the general population,” The Lancet Diabetes & Endocrinology, vol. 6, no. 4, pp. 319–331, 2018. View at: Publisher Site | Google Scholar
  147. J. P. Kooman, F. M. van der Sande, and K. M. L. Leunissen, “Kidney disease and aging: a reciprocal relation,” Experimental Gerontology., vol. 87, Part B, pp. 156–159, 2017. View at: Publisher Site | Google Scholar
  148. K. D. Burns, “Angiotensin II and its receptors in the diabetic kidney,” American Journal of Kidney Diseases, vol. 36, no. 3, pp. 449–467, 2000. View at: Publisher Site | Google Scholar
  149. Y.-C. Lin, Y.-H. Chang, S.-Y. Yang, K.-D. Wu, and T.-S. Chu, “Update of pathophysiology and management of diabetic kidney disease,” Journal of the Formosan Medical Association, vol. 117, no. 8, pp. 662–675, 2018. View at: Publisher Site | Google Scholar
  150. Y. Wang, S. Yang, Q. Zhou, H. Zhang, and B. Yi, “Effects of vitamin D supplementation on renal function, inflammation and glycemic control in patients with diabetic nephropathy: a systematic review and meta-analysis,” Kidney & Blood Pressure Research, vol. 44, no. 1, pp. 72–87, 2019. View at: Publisher Site | Google Scholar
  151. L.-L. Han, X.-J. Bai, H.-L. Lin, X.-F. Sun, and X.-M. Chen, “Association between kidney and cardiac diastolic function in Chinese subjects without overt disease: correlation with ageing and inflammatory markers,” European Journal of Clinical Investigation, vol. 41, no. 10, pp. 1077–1086, 2011. View at: Publisher Site | Google Scholar
  152. C. D’Alessandro, G. Piccoli, M. Barsotti et al., “Prevalence and correlates of sarcopenia among elderly CKD outpatients on tertiary care,” Nutrients, vol. 10, no. 12, article 1951, 2018. View at: Publisher Site | Google Scholar
  153. D. Bolignano, F. Mattace-Raso, E. J. G. Sijbrands, and C. Zoccali, “The aging kidney revisited: a systematic review,” Ageing Research Reviews, vol. 14, pp. 65–80, 2014. View at: Publisher Site | Google Scholar
  154. S. H. McKiernan, V. C. Tuen, K. Baldwin, J. Wanagat, A. Djamali, and J. M. Aiken, “Adult-onset calorie restriction delays the accumulation of mitochondrial enzyme abnormalities in aging rat kidney tubular epithelial cells,” American Journal of Physiology-Renal Physiology, vol. 292, no. 6, pp. F1751–F1760, 2007. View at: Publisher Site | Google Scholar
  155. Y.-C. Ning, G.-Y. Cai, L. Zhuo et al., “Short-term calorie restriction protects against renal senescence of aged rats by increasing autophagic activity and reducing oxidative damage,” Mechanisms of Ageing and Development, vol. 134, no. 11-12, pp. 570–579, 2013. View at: Publisher Site | Google Scholar
  156. D. Dong, G. Y. Cai, Y. C. Ning et al., “Alleviation of senescence and epithelial-mesenchymal transition in aging kidney by short-term caloric restriction and caloric restriction mimetics via modulation of AMPK/mTOR signaling,” Oncotarget, vol. 8, no. 10, pp. 16109–16121, 2017. View at: Publisher Site | Google Scholar
  157. K. J. Jung, E. K. Lee, J. Y. Kim et al., “Effect of short term calorie restriction on pro-inflammatory NF-kB and AP-1 in aged rat kidney,” Inflammation Research, vol. 58, no. 3, pp. 143–150, 2009. View at: Publisher Site | Google Scholar
  158. J. H. Lee, K. J. Jung, J. W. Kim, H. J. Kim, B. P. Yu, and H. Y. Chung, “Suppression of apoptosis by calorie restriction in aged kidney,” Experimental Gerontology, vol. 39, no. 9, pp. 1361–1368, 2004. View at: Publisher Site | Google Scholar
  159. P. Ruggenenti, M. Abbate, B. Ruggiero et al., “Renal and systemic effects of calorie restriction in patients with type 2 diabetes with abdominal obesity: a randomized controlled trial,” Diabetes, vol. 66, no. 1, pp. 75–86, 2016. View at: Publisher Site | Google Scholar
  160. L. L. Velazquez, A. M. Sil, R. M. Goycochea, T. M. Torres, and L. R. Castaneda, “Effect of protein restriction diet on renal function and metabolic control in patients with type 2 diabetes: a randomized clinical trial,” Nutrición Hospitalaria, vol. 23, pp. 141–147, 2008. View at: Google Scholar
  161. B. Dussol, C. Iovanna, D. Raccah et al., “A randomized trial of low-protein diet in type 1 and in type 2 diabetes mellitus patients with incipient and overt nephropathy,” Journal of Renal Nutrition, vol. 15, no. 4, pp. 398–406, 2005. View at: Publisher Site | Google Scholar
  162. A. Sattarinezhad, J. Roozbeh, B. Shirazi Yeganeh, G. R. Omrani, and M. Shams, “Resveratrol reduces albuminuria in diabetic nephropathy: a randomized double- blind placebo-controlled clinical trial,” Diabetes & Metabolism, vol. 45, no. 1, pp. 53–59, 2019. View at: Publisher Site | Google Scholar
  163. M. M. A. Hussein and M. K. Mahfouz, “Effect of resveratrol and rosuvastatin on experimental diabetic nephropathy in rats,” Biomedicine & Pharmacotherapy, vol. 82, pp. 685–692, 2016. View at: Publisher Site | Google Scholar
  164. T. Zhang, Y. Chi, Y. Ren, C. Du, Y. Shi, and Y. Li, “Resveratrol reduces oxidative stress and apoptosis in podocytes via Sir2-related enzymes, sirtuins1 (SIRT1)/peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α) Axis,” Medical Science Monitor, vol. 25, pp. 1220–1231, 2019. View at: Publisher Site | Google Scholar
  165. L. Wu, Y. Zhang, X. Ma, N. Zhang, and G. Qin, “The effect of resveratrol on FoxO1 expression in kidneys of diabetic nephropathy rats,” Molecular Biology Reports, vol. 39, no. 9, pp. 9085–9093, 2012. View at: Publisher Site | Google Scholar
  166. W. S. Cheang, W. T. Wong, L. Wang et al., “Resveratrol ameliorates endothelial dysfunction in diabetic and obese mice through sirtuin 1 and peroxisome proliferator-activated receptor δ,” Pharmacological Research, vol. 139, pp. 384–394, 2019. View at: Publisher Site | Google Scholar
  167. Y. Qiao, K. Gao, Y. Wang, X. Wang, and B. Cui, “Resveratrol ameliorates diabetic nephropathy in rats through negative regulation of the p38 MAPK/TGF-β1 pathway,” Experimental and Therapeutic Medicine, vol. 13, no. 6, pp. 3223–3230, 2017. View at: Publisher Site | Google Scholar
  168. F. Abharzanjani, M. Afshar, M. Hemmati, and M. Moossavi, “Short-term high dose of quercetin and resveratrol alters aging markers in human kidney cells,” International Journal of Preventive Medicine, vol. 8, p. 64, 2017. View at: Google Scholar
  169. W. H. Hsu, P.-J. Hsiao, P.-C. Lin, S.-C. Chen, M.-Y. Lee, and S.-J. Shin, “Effect of metformin on kidney function in patients with type 2 diabetes mellitus and moderate chronic kidney disease,” Oncotarget, vol. 9, no. 4, pp. 5416–5423, 2018. View at: Publisher Site | Google Scholar
  170. E. O. Gosmanova, S. R. Shahzad, K. Sumida, C. P. Kovesdy, and A. R. Gosmanov, “Metformin is associated with increase in lactate level in elderly patients with type 2 diabetes and CKD stage 3: a case-control study,” Journal of Diabetes and its Complications, vol. 34, no. 1, article 107474, 2020. View at: Publisher Site | Google Scholar
  171. D. M. Charytan, S. D. Solomon, P. Ivanovich et al., “Metformin use and cardiovascular events in patients with type 2 diabetes and chronic kidney disease,” Diabetes, Obesity & Metabolism, vol. 21, no. 5, pp. 1199–1208, 2019. View at: Publisher Site | Google Scholar
  172. E. Neven, B. Vervaet, K. Brand et al., “Metformin prevents the development of severe chronic kidney disease and its associated mineral and bone disorder,” Kidney International, vol. 94, no. 1, pp. 102–113, 2018. View at: Publisher Site | Google Scholar
  173. W. M. Valencia, A. Palacio, L. Tamariz, and H. Florez, “Metformin and ageing: improving ageing outcomes beyond glycaemic control,” Diabetologia, vol. 60, no. 9, pp. 1630–1638, 2017. View at: Publisher Site | Google Scholar
  174. N. Barzilai, J. P. Crandall, S. B. Kritchevsky, and M. A. Espeland, “Metformin as a tool to target aging,” Cell Metabolism, vol. 23, no. 6, pp. 1060–1065, 2016. View at: Publisher Site | Google Scholar
  175. J. M. Miles, A. D. Rule, and B. A. Borlaug, “Use of metformin in diseases of aging,” Current Diabetes Reports, vol. 14, no. 6, p. 490, 2014. View at: Publisher Site | Google Scholar
  176. J. M. Campbell, S. M. Bellman, M. D. Stephenson, and K. Lisy, “Metformin reduces all-cause mortality and diseases of ageing independent of its effect on diabetes control: a systematic review and meta-analysis,” Ageing Research Reviews, vol. 40, pp. 31–44, 2017. View at: Publisher Site | Google Scholar
  177. A. Eisenreich and U. Leppert, “Update on the protective renal effects of metformin in diabetic nephropathy,” Current Medicinal Chemistry, vol. 24, no. 31, pp. 3397–3412, 2017. View at: Publisher Site | Google Scholar
  178. S. Langer, R. Kreutz, and A. Eisenreich, “Metformin modulates apoptosis and cell signaling of human podocytes under high glucose conditions,” Journal of Nephrology, vol. 29, no. 6, pp. 765–773, 2016. View at: Publisher Site | Google Scholar
  179. A. Piwkowska, D. Rogacka, M. Jankowski, and S. Angielski, “Metformin reduces NAD(P)H oxidase activity in mouse cultured podocytes through purinergic dependent mechanism by increasing extracellular ATP concentration,” Acta Biochimica Polonica, vol. 60, no. 4, pp. 607–612, 2013. View at: Google Scholar
  180. L. Zhai, J. Gu, D. Yang, W. Hu, W. Wang, and S. Ye, “Metformin ameliorates podocyte damage by restoring renal tissue nephrin expression in type 2 diabetic rats,” Journal of Diabetes, vol. 9, no. 5, pp. 510–517, 2017. View at: Publisher Site | Google Scholar
  181. J. Kim, E. Shon, C. S. Kim, and J. S. Kim, “Renal podocyte injury in a rat model of type 2 diabetes is prevented by metformin,” Experimental Diabetes Research, vol. 2012, Article ID 210821, 9 pages, 2012. View at: Publisher Site | Google Scholar
  182. D. Rogacka, I. Audzeyenka, M. Rychlowski et al., “Metformin overcomes high glucose-induced insulin resistance of podocytes by pleiotropic effects on SIRT1 and AMPK,” Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, vol. 1864, no. 1, pp. 115–125, 2018. View at: Publisher Site | Google Scholar
  183. J. Gu, S. Ye, W. Shan, W. Sun, and Y. Hu, “Metformin inhibits nuclear factor-κB activation and inflammatory cytokines expression induced by high glucose via adenosine monophosphate-activated protein kinase activation in rat glomerular mesangial cells in vitro,” National Medical Journal of China, vol. 127, pp. 1755–1760, 2014. View at: Google Scholar
  184. Z. Kang, J. Zeng, T. Zhang et al., “Hyperglycemia induces NF‐κB activation and MCP-1 expression via downregulating GLP-1R expression in rat mesangial cells: inhibition by metformin,” Cell Biology International, vol. 43, no. 8, pp. 940–953, 2019. View at: Publisher Site | Google Scholar
  185. H. Ren, Y. Shao, C. Wu, X. Ma, C. Lv, and Q. Wang, “Metformin alleviates oxidative stress and enhances autophagy in diabetic kidney disease via AMPK/SIRT1-FoxO1 pathway,” Molecular and Cellular Endocrinology, vol. 500, article 110628, 2020. View at: Publisher Site | Google Scholar
  186. J. Xu, L. Q. Liu, L. L. Xu, Y. Xing, and S. Ye, “Metformin alleviates renal injury in diabetic rats by inducing Sirt1/FoxO1 autophagic signal axis,” Clinical and Experimental Pharmacology & Physiology, vol. 47, no. 4, pp. 599–608, 2020. View at: Publisher Site | Google Scholar
  187. S. Allouch and S. Munusamy, “Metformin attenuates albumin-induced alterations in renal tubular cells in vitro,” Journal of Cellular Physiology, vol. 232, no. 12, pp. 3652–3663, 2017. View at: Publisher Site | Google Scholar
  188. S. Y. Lee, J. M. Kang, D. J. Kim et al., “PGC1α activators mitigate diabetic Tubulopathy by improving mitochondrial dynamics and quality control,” Journal Diabetes Research, vol. 2017, article 6483572, 15 pages, 2017. View at: Publisher Site | Google Scholar
  189. Y.-N. Guo, J.-C. Wang, G.-Y. Cai et al., “AMPK-mediated downregulation of connexin43 and premature senescence of mesangial cells under high-glucose conditions,” Experimental Gerontology, vol. 51, pp. 71–81, 2014. View at: Publisher Site | Google Scholar
  190. Z. Molnar, A. B. Millward, W. Tse, and A. G. Demaine, “p21WAF1/CIP1 expression is differentially regulated by metformin and rapamycin,” International Journal of Chronic Diseases, vol. 2014, Article ID 327640, 17 pages, 2014. View at: Publisher Site | Google Scholar
  191. V. Perkovic, M. J. Jardine, B. Neal et al., “Canagliflozin and renal outcomes in type 2 diabetes and nephropathy,” The New England Journal of Medicine, vol. 380, no. 24, pp. 2295–2306, 2019. View at: Publisher Site | Google Scholar
  192. S. Khemais‐Benkhiat, E. Belcastro, N. Idris‐Khodja et al., “Angiotensin II-induced redox-sensitive SGLT1 and 2 expression promotes high glucose-induced endothelial cell senescence,” Journal of Cellular and Molecular Medicine., vol. 24, no. 3, pp. 2109–2122, 2020. View at: Publisher Site | Google Scholar
  193. D. Zhang, M. Ma, and Y. Liu, “Protective effects of incretin against age-related diseases,” Current Drug Delivery, vol. 16, no. 9, pp. 793–806, 2019. View at: Publisher Site | Google Scholar
  194. Y. Hasegawa, K. Hayashi, Y. Takemoto et al., “DPP-4 inhibition with linagliptin ameliorates the progression of premature aging in klotho-/- mice,” Cardiovascular Diabetology, vol. 16, no. 1, p. 154, 2017. View at: Publisher Site | Google Scholar
  195. G. Coppolino, C. Leporini, L. Rivoli et al., “Exploring the effects of DPP-4 inhibitors on the kidney from the bench to clinical trials,” Pharmacological Research, vol. 129, pp. 274–294, 2018. View at: Publisher Site | Google Scholar
  196. X. W. Cheng, M. Narisawa, E. Jin, C. Yu, W. Xu, and L. Piao, “Dose rectification of an imbalance between DPP4 and GLP-1 ameliorates chronic stress-related vascular aging and atherosclerosis?” Clinical and Experimental Pharmacology & Physiology, vol. 45, no. 5, pp. 467–470, 2018. View at: Publisher Site | Google Scholar
  197. J. X. Shi and Q. Huang, “Glucagon‑like peptide‑1 protects mouse podocytes against high glucose‑induced apoptosis, and suppresses reactive oxygen species production and proinflammatory cytokine secretion, through sirtuin 1 activation in vitro,” Molecular Medicine Reports, vol. 18, no. 2, pp. 1789–1797, 2018. View at: Publisher Site | Google Scholar
  198. J. Moellmann, B. M. Klinkhammer, J. Onstein et al., “Glucagon-like peptide 1 and its cleavage products are renoprotective in murine diabetic nephropathy,” Diabetes, vol. 67, no. 11, pp. 2410–2419, 2018. View at: Publisher Site | Google Scholar
  199. J. Yang, Y. Zhou, and Y. Guan, “PPARγ as a therapeutic target in diabetic nephropathy and other renal diseases,” Current Opinion in Nephrology and Hypertension, vol. 21, no. 1, pp. 97–105, 2012. View at: Publisher Site | Google Scholar
  200. D. Shen, H. Li, R. Zhou, M.-j. Liu, H. Yu, and D.-F. Wu, “Pioglitazone attenuates aging-related disorders in aged apolipoprotein E deficient mice,” Experimental Gerontology, vol. 102, pp. 101–108, 2018. View at: Publisher Site | Google Scholar
  201. H.-C. Yang, S. Deleuze, Y. Zuo, S. A. Potthoff, L.-J. Ma, and A. B. Fogo, “The PPARγ agonist pioglitazone ameliorates aging-related progressive renal injury,” Journal of the American Society of Nephrology, vol. 20, no. 11, pp. 2380–2388, 2009. View at: Publisher Site | Google Scholar
  202. P. Pourshabanan, A. Momeni, L. Mahmoudnia, and S. Kheiri, “Effect of pioglitazone on decreasing of proteinuria in type 2 diabetic patients with nephropathy,” Diabetes and Metabolic Syndrome: Clinical Research and Reviews, vol. 13, pp. 132–136, 2019. View at: Google Scholar
  203. B. Satirapoj, K. Watanakijthavonkul, and O. Supasyndh, “Safety and efficacy of low dose pioglitazone compared with standard dose pioglitazone in type 2 diabetes with chronic kidney disease: a randomized controlled trial,” PLoS One, vol. 13, no. 10, article e0206722, 2018. View at: Publisher Site | Google Scholar
  204. D. Bolignano, V. Cernaro, G. Gembillo, R. Baggetta, M. Buemi, and G. D’Arrigo, “Antioxidant agents for delaying diabetic kidney disease progression: a systematic review and meta-analysis,” PLoS One, vol. 12, no. 6, article e0178699, 2017. View at: Publisher Site | Google Scholar
  205. E. Aghadavod, A. Soleimani, G. Hamidi, F. Keneshlou, A. Heidari, and Z. Asemi, “Effects of high-dose vitamin E supplementation on markers of cardiometabolic risk and oxidative stress in patients with diabetic nephropathy: a randomized double-blinded controlled trial,” Iranian Journal of Kidney Diseases, vol. 12, p. 156, 2018. View at: Google Scholar
  206. E. F. Fang, S. Lautrup, Y. Hou et al., “NAD+ in aging: molecular mechanisms and translational implications,” Trends in Molecular Medicine, vol. 23, no. 10, pp. 899–916, 2017. View at: Publisher Site | Google Scholar
  207. K. Okabe, K. Yaku, K. Tobe, and T. Nakagawa, “Implications of altered NAD metabolism in metabolic disorders,” Journal of Biomedical Science, vol. 26, no. 1, p. 34, 2019. View at: Publisher Site | Google Scholar
  208. E. F. Fang, H. Kassahun, D. L. Croteau et al., “NAD+ replenishment improves lifespan and healthspan in ataxia telangiectasia models via mitophagy and DNA repair,” Cell Metabolism., vol. 24, no. 4, pp. 566–581, 2016. View at: Publisher Site | Google Scholar
  209. T. Nacarelli, L. Lau, T. Fukumoto et al., “NAD+ metabolism governs the proinflammatory senescence-associated secretome,” Nature Cell Biology, vol. 21, no. 3, pp. 397–407, 2019. View at: Publisher Site | Google Scholar
  210. B. G. Childs, M. Gluscevic, D. J. Baker et al., “Senescent cells: an emerging target for diseases of ageing,” Nature reviews Drug discovery, vol. 16, no. 10, pp. 718–735, 2017. View at: Publisher Site | Google Scholar
  211. S. He and N. E. Sharpless, “Senescence in health and disease,” Cell, vol. 169, no. 6, pp. 1000–1011, 2017. View at: Publisher Site | Google Scholar
  212. S. Short, E. Fielder, S. Miwa, and T. von Zglinicki, “Senolytics and senostatics as adjuvant tumour therapy,” eBioMedicine, vol. 41, pp. 683–692, 2019. View at: Publisher Site | Google Scholar
  213. J. N. Justice, A. M. Nambiar, T. Tchkonia et al., “Senolytics in idiopathic pulmonary fibrosis: results from a first-in-human, open-label, pilot study,” eBioMedicine, vol. 40, pp. 554–563, 2019. View at: Publisher Site | Google Scholar
  214. P. Zhang, Y. Kishimoto, I. Grammatikakis et al., “Senolytic therapy alleviates Aβ-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer’s disease model,” Nature Neuroscience., vol. 22, pp. 719–728, 2019. View at: Google Scholar
  215. S. N. Knoppert, F. A. Valentijn, T. Q. Nguyen, R. Goldschmeding, and L. L. Falke, “Cellular senescence and the kidney: potential therapeutic targets and tools,” Frontiers in Pharmacology, vol. 10, p. 770, 2019. View at: Publisher Site | Google Scholar
  216. L. T. J. Hickson, L. G. P. Langhi Prata, S. A. Bobart et al., “Senolytics decrease senescent cells in humans: preliminary report from a clinical trial of dasatinib plus quercetin in individuals with diabetic kidney disease,” eBioMedicine, vol. 47, pp. 446–456, 2019. View at: Publisher Site | Google Scholar
  217. M. V. Blagosklonny, “Paradoxes of senolytics,” Aging, vol. 10, no. 12, pp. 4289–4293, 2018. View at: Publisher Site | Google Scholar
  218. B. Fu, J. Yang, J. Chen et al., “Preventive effect of Shenkang injection against high glucose-induced senescence of renal tubular cells,” Frontiers of Medicine, vol. 13, pp. 267–272, 2018. View at: Google Scholar
  219. A. Bielak-Zmijewska, W. Grabowska, A. Ciolko et al., “The role of curcumin in the modulation of ageing,” International Journal of Molecular Sciences., vol. 20, article E1239, 2019. View at: Google Scholar
  220. W. Li, Y. He, R. Zhang, G. Zheng, and D. Zhou, “The curcumin analog EF24 is a novel senolytic agent,” Aging, vol. 11, pp. 771–782, 2019. View at: Google Scholar
  221. N. N. Ulusu, M. Gök, A. A. S. Şakul, N. Ari, M. Stefek, and Ç. Karasu, “Antioxidant SMe1EC2 modulates pentose phosphate pathway and glutathione-dependent enzyme activities in tissues of aged diabetic rats,” Interdisciplinary Toxicology, vol. 10, no. 4, pp. 148–154, 2017. View at: Publisher Site | Google Scholar
  222. D. Cao, M. Zhao, C. Wan et al., “Role of tea polyphenols in delaying hyperglycemia-induced senescence in human glomerular mesangial cells via miR-126/Akt–p53–p21 pathways,” International Urology and Nephrology., vol. 51, no. 6, pp. 1071–1078, 2019. View at: Publisher Site | Google Scholar
  223. Z. Xu, W. Feng, Q. Shen et al., “Rhizoma coptidis and berberine as a natural drug to combat aging and aging-related diseases via anti-oxidation and AMPK activation,” Aging and Disease, vol. 8, no. 6, pp. 760–777, 2017. View at: Publisher Site | Google Scholar
  224. L. In Hye, C. Liu, M. Raul et al., “A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy,” Proceedings of the National Academy of Sciences, vol. 105, pp. 3374–3379, 2008. View at: Google Scholar
  225. Á. F. Fernández, S. Sebti, Y. Wei et al., “Disruption of the beclin 1-BCL2 autophagy regulatory complex promotes longevity in mice,” Nature, vol. 558, no. 7708, pp. 136–140, 2018. View at: Publisher Site | Google Scholar
  226. S. W. Lim, Y. J. Shin, K. Luo et al., “Effect of klotho on autophagy clearance in tacrolimus-induced renal injury,” The FASEB Journal, vol. 33, pp. 2694–2706, 2018. View at: Google Scholar
  227. J.-P. Coppé, P.-Y. Desprez, A. Krtolica, and J. Campisi, “The senescence-associated secretory phenotype: the dark side of tumor suppression,” Annual Review of Pathology, vol. 5, no. 1, pp. 99–118, 2010. View at: Publisher Site | Google Scholar
  228. M. S. Chang and Y. H. Hsu, “The role of IL-20 in chronic kidney disease and diabetic nephropathy: pathogenic and therapeutic implications,” Journal of Leukocyte Biology, vol. 104, no. 5, pp. 919–923, 2018. View at: Publisher Site | Google Scholar
  229. S. A. Fathy, M. R. Mohamed, M. A. M. Ali, A. E. El-Helaly, and A. T. Alattar, “Influence of IL-6, IL-10, IFN-γ and TNF-α genetic variants on susceptibility to diabetic kidney disease in type 2 diabetes mellitus patients,” Biomarkers, vol. 24, pp. 43–45, 2018. View at: Google Scholar
  230. I. B. M. Kolseth, T. M. Reine, K. Parker et al., “Increased levels of inflammatory mediators and proinflammatory monocytes in patients with type I diabetes mellitus and nephropathy,” Journal of Diabetes and its Complications, vol. 31, no. 1, pp. 245–252, 2017. View at: Publisher Site | Google Scholar
  231. J. Ma, Y. J. Li, X. Chen, T. Kwan, S. J. Chadban, and H. Wu, “Interleukin 17A promotes diabetic kidney injury,” Scientific Reports, vol. 9, no. 1, p. 2264, 2019. View at: Publisher Site | Google Scholar
  232. S. S. Nawaz, S. S. Joy, Y. Al Farsi, T. P. George, and K. Siddiqui, “Potential role of serum fetuin-a in relation with pro-inflammatory, chemokine and adhesion molecules in diabetic kidney disease: a case–control study,” Molecular Biology Reports, vol. 46, no. 1, pp. 1239–1246, 2019. View at: Publisher Site | Google Scholar
  233. E. Sierra-Mondragon, E. Molina-Jijon, C. Namorado-Tonix, R. Rodríguez-Muñoz, J. Pedraza-Chaverri, and J. L. Reyes, “All-trans retinoic acid ameliorates inflammatory response mediated by TLR4/NF- κB during initiation of diabetic nephropathy,” The Journal of Nutritional Biochemistry, vol. 60, pp. 47–60, 2018. View at: Publisher Site | Google Scholar
  234. B.-I. So, Y.-S. Song, C.-H. Fang et al., “G-CSF prevents progression of diabetic nephropathy in rat,” PLoS One, vol. 8, no. 10, article e77048, 2013. View at: Publisher Site | Google Scholar
  235. M. Sun, W. Bu, Y. Li et al., “Danzhi Jiangtang capsule ameliorates kidney injury via inhibition of the JAK-STAT signaling pathway and increased antioxidant capacity in STZ-induced diabetic nephropathy rats,” BioScience Trends, vol. 12, no. 6, pp. 595–604, 2018. View at: Publisher Site | Google Scholar
  236. Y.-C. Tsai, P.-L. Kuo, M.-C. Kuo et al., “The interaction of miR-378i-Skp2 regulates cell senescence in diabetic nephropathy,” Journal of Clinical Medicine, vol. 7, no. 12, p. 468, 2018. View at: Publisher Site | Google Scholar
  237. Z. Wang, M. Wei, M. Wang et al., “Inhibition of macrophage migration inhibitory factor reduces diabetic nephropathy in type II diabetes mice,” Inflammation, vol. 37, no. 6, pp. 2020–2029, 2014. View at: Publisher Site | Google Scholar
  238. H.-l. Xu, X.-t. Wang, Y. Cheng et al., “Ursolic acid improves diabetic nephropathy _via_ suppression of oxidative stress and inflammation in streptozotocin-induced rats,” Biomedicine & Pharmacotherapy, vol. 105, pp. 915–921, 2018. View at: Publisher Site | Google Scholar
  239. K. Xu, L. Guo, H. Bu, and H. Wang, “Daphnetin inhibits high glucose-induced extracellular matrix accumulation, oxidative stress and inflammation in human glomerular mesangial cells,” Journal of Pharmacological Sciences, vol. 139, no. 2, pp. 91–97, 2019. View at: Publisher Site | Google Scholar
  240. L. Valiño-Rivas, L. Cuarental, O. Grana et al., “TWEAK increases CD74 expression and sensitizes to DDT proinflammatory actions in tubular cells,” PLoS One, vol. 13, no. 6, article e0199391, 2018. View at: Publisher Site | Google Scholar
  241. M. S. Roy, M. N. Janal, J. Crosby, and R. Donnelly, “Markers of endothelial dysfunction and inflammation predict progression of diabetic nephropathy in African Americans with type 1 diabetes,” Kidney International, vol. 87, no. 2, pp. 427–433, 2015. View at: Publisher Site | Google Scholar
  242. Y. Takamiya, K. Fukami, S.-i. Yamagishi et al., “Experimental diabetic nephropathy is accelerated in matrix metalloproteinase-2 knockout mice,” Nephrology Dialysis Transplantation, vol. 28, no. 1, pp. 55–62, 2013. View at: Publisher Site | Google Scholar
  243. J. Wu, C. Mei, H. Vlassara, G. E. Striker, and F. Zheng, “Oxidative stress-induced JNK activation contributes to proinflammatory phenotype of aging diabetic mesangial cells,” American Journal of Physiology-Renal Physiology, vol. 297, no. 6, pp. F1622–F1631, 2009. View at: Publisher Site | Google Scholar
  244. D. Zha, T. Yao, L. Bao, P. Gao, and X. Wu, “Telmisartan attenuates diabetic nephropathy progression by inhibiting the dimerization of angiotensin type-1 receptor and adiponectin receptor-1,” Life Sciences, vol. 221, pp. 109–120, 2019. View at: Publisher Site | Google Scholar
  245. B. Yi, X. Hu, H. Zhang et al., “Nuclear NF-κB p65 in peripheral blood mononuclear cells correlates with urinary MCP-1, RANTES and the severity of type 2 diabetic nephropathy,” PLoS One, vol. 9, no. 6, article e99633, 2014. View at: Publisher Site | Google Scholar
  246. J. Lv, Z. Wang, Y. Wang et al., “Renoprotective effect of the Shen-Yan-Fang-Shuai formula by inhibiting TNF-α/NF-κB signaling pathway in diabetic rats,” Journal of Diabetes Research, vol. 2017, Article ID 4319057, 11 pages, 2017. View at: Publisher Site | Google Scholar
  247. J. Watanabe, Y. Takiyama, J. Honjyo et al., “Role of IGFBP7 in diabetic nephropathy: TGF-β1 induces IGFBP7 via Smad2/4 in human renal proximal tubular epithelial cells,” PLoS One, vol. 11, no. 3, article e0150897, 2016. View at: Publisher Site | Google Scholar
  248. Z. Zhang, L. Li, Z. K. Li et al., “Effect and mechanism of mulberry leaf polysaccharide on type 1 diabetic nephropathy in rats,” Zhonghua Yi Xue Za Zhi, vol. 98, no. 22, pp. 1792–1796, 2018. View at: Publisher Site | Google Scholar
  249. A. M. El-Saeed and G. F. El-Mohasseb, “Circulating fibroblast growth factors 21 and 23 as biomarkers of progression in diabetic nephropathy in type 2 diabetes with normoalbuminuria,” The Egyptian Journal of Immunology, vol. 24, no. 2, pp. 93–99, 2017. View at: Google Scholar
  250. A. Farías-Basulto, H. R. Martínez-Ramírez, E. F. Gómez-García et al., “Circulating levels of soluble klotho and fibroblast growth factor 23 in diabetic patients and its association with early nephropathy,” Archives of Medical Research, vol. 49, no. 7, pp. 451–455, 2018. View at: Publisher Site | Google Scholar
  251. G. Cakirca and F. H. Turgut, “Serum matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1 and matrix metalloproteinase-9/neutrophil gelatinase-associated lipocalin complex levels in patients with early-stage diabetic nephropathy,” Iranian Journal of Kidney Diseases, vol. 12, no. 5, pp. 299–304, 2018. View at: Google Scholar
  252. A. U. Garcia-Tejeda, C. L. Sampieri, I. Suarez-Torres et al., “Association of urinary activity of MMP-9 with renal impairment in Mexican patients with type 2 diabetes mellitus,” PeerJ, vol. 6, article e6067, 2018. View at: Publisher Site | Google Scholar
  253. F.-N. Yu, M.-L. Hu, X.-F. Wang et al., “Effects of microRNA-370 on mesangial cell proliferation and extracellular matrix accumulation by binding to canopy 1 in a rat model of diabetic nephropathy,” Journal of Cellular Physiology, vol. 234, no. 5, pp. 6898–6907, 2019. View at: Publisher Site | Google Scholar
  254. H. Yaribeygi, M. T. Mohammadi, R. Rezaee, and A. Sahebkar, “Fenofibrate improves renal function by amelioration of NOX-4, IL-18, and p53 expression in an experimental model of diabetic nephropathy,” Journal of Cellular Biochemistry, vol. 119, pp. 7458–7469, 2018. View at: Google Scholar
  255. T. He, J. Xiong, L. Nie et al., “Resveratrol inhibits renal interstitial fibrosis in diabetic nephropathy by regulating AMPK/NOX4/ROS pathway,” Journal of Molecular Medicine, vol. 94, no. 12, pp. 1359–1371, 2016. View at: Publisher Site | Google Scholar
  256. F. Xu, Y. Wang, W. Cui et al., “Resveratrol prevention of diabetic nephropathy is associated with the suppression of renal inflammation and mesangial cell proliferation: possible roles of Akt/NF-kappaB pathway,” International Journal of Endocrinology, vol. 2014, Article ID 289327, 9 pages, 2014. View at: Publisher Site | Google Scholar
  257. Y. Xu, L. Nie, Y.-G. Yin et al., “Resveratrol protects against hyperglycemia-induced oxidative damage to mitochondria by activating SIRT1 in rat mesangial cells,” Toxicology and Applied Pharmacology, vol. 259, no. 3, pp. 395–401, 2012. View at: Publisher Site | Google Scholar
  258. H. Moridi, J. Karimi, N. Sheikh et al., “Resveratrol-dependent down-regulation of receptor for advanced glycation end-products and oxidative stress in kidney of rats with diabetes,” International Journal of Endocrinology and Metabolism, vol. 13, article e23542, 2015. View at: Google Scholar
  259. H. S. Park, J. H. Lim, M. Y. Kim et al., “Resveratrol increases AdipoR1 and AdipoR2 expression in type 2 diabetic nephropathy,” Journal of Translational Medicine, vol. 14, no. 1, p. 176, 2016. View at: Publisher Site | Google Scholar
  260. M. Y. Kim, J. H. Lim, H. H. Youn et al., “Resveratrol prevents renal lipotoxicity and inhibits mesangial cell glucotoxicity in a manner dependent on the AMPK–SIRT1–PGC1α axis in db/db mice,” Diabetologia, vol. 56, no. 1, pp. 204–217, 2013. View at: Publisher Site | Google Scholar
  261. X. H. Xu, D. F. Ding, H. J. Yong et al., “Resveratrol transcriptionally regulates miRNA-18a-5p expression ameliorating diabetic nephropathy via increasing autophagy,” European Review for Medical and Pharmacological Sciences, vol. 21, pp. 4952–4965, 2017. View at: Google Scholar
  262. S. S. Huang, D. F. Ding, S. Chen et al., “Resveratrol protects podocytes against apoptosis via stimulation of autophagy in a mouse model of diabetic nephropathy,” Scientific Reports, vol. 7, no. 1, p. 45692, 2017. View at: Publisher Site | Google Scholar
  263. D. Yuan, X. M. Liu, Z. Fang, L. L. Du, J. Chang, and S. H. Lin, “Protective effect of resveratrol on kidney in rats with diabetic nephropathy and its effect on endoplasmic reticulum stress,” European Review for Medical and Pharmacological Sciences, vol. 22, no. 5, pp. 1485–1493, 2018. View at: Publisher Site | Google Scholar
  264. S. Zhang, H. Xu, X. Yu, Y. Wu, and D. Sui, “Metformin ameliorates diabetic nephropathy in a rat model of low-dose streptozotocin-induced diabetes,” Experimental and Therapeutic Medicine, vol. 14, no. 1, pp. 383–390, 2017. View at: Publisher Site | Google Scholar
  265. X. M. Yao, S. D. Ye, C. C. Xiao, J. F. Gu, D. Yang, and S. Wang, “Metformin alleviates high glucose-mediated oxidative stress in rat glomerular mesangial cells by modulation of p38 mitogen-activated protein kinase expression in vitro,” Molecular Medicine Reports, vol. 12, pp. 520–526, 2015. View at: Google Scholar
  266. Y. Ishibashi, T. Matsui, M. Takeuchi, and S. Yamagishi, “Metformin inhibits advanced glycation end products (AGEs)-induced renal tubular cell injury by suppressing reactive oxygen species generation via reducing receptor for AGEs (RAGE) expression,” Hormone and Metabolic Research, vol. 44, no. 12, pp. 891–895, 2012. View at: Publisher Site | Google Scholar
  267. M. Christensen, T. A. Schiffer, H. Gustafsson, S. P. Krag, R. Nørregaard, and F. Palm, “Metformin attenuates renal medullary hypoxia in diabetic nephropathy through inhibition uncoupling protein-2,” Diabetes/Metabolism Research and Reviews, vol. 35, no. 2, article e3091, 2019. View at: Publisher Site | Google Scholar
  268. M. Guan, W. Li, L. Xu et al., “Metformin improves epithelial-to-mesenchymal transition induced by TGF-β1 in renal tubular epithelial NRK-52E cells via inhibiting Egr-1,” Journal Diabetes Research, vol. 2018, article 1031367, 8 pages, 2018. View at: Publisher Site | Google Scholar
  269. D. Liang, Z. Song, W. Liang, Y. Li, and S. Liu, “Metformin inhibits TGF-beta 1-induced MCP-1 expression through BAMBI-mediated suppression of MEK/ERK1/2 signalling,” Nephrology (Carlton), vol. 24, no. 4, pp. 481–488, 2019. View at: Publisher Site | Google Scholar
  270. Y. Jia, Z. Zheng, M. Guan et al., “Exendin-4 ameliorates high glucose-induced fibrosis by inhibiting the secretion of miR-192 from injured renal tubular epithelial cells,” Experimental & Molecular Medicine, vol. 50, no. 5, pp. 1–13, 2018. View at: Publisher Site | Google Scholar
  271. W.-W. Xu, M.-P. Guan, Z.-J. Zheng et al., “Exendin-4 alleviates high glucose-induced rat mesangial cell dysfunction through the AMPK pathway,” Cellular Physiology and Biochemistry, vol. 33, no. 2, pp. 423–432, 2014. View at: Publisher Site | Google Scholar
  272. T. Zitman-Gal, Y. Einbinder, M. Ohana, A. Katzav, A. Kartawy, and S. Benchetrit, “Effect of liraglutide on the Janus kinase/signal transducer and transcription activator (JAK/STAT) pathway in diabetic kidney disease in db/db mice and in cultured endothelial cells,” Journal of Diabetes, vol. 11, no. 8, pp. 656–664, 2019. View at: Publisher Site | Google Scholar
  273. P. Chen, X. Shi, X. Xu et al., “Liraglutide ameliorates early renal injury by the activation of renal FoxO1 in a type 2 diabetic kidney disease rat model,” Diabetes Research and Clinical Practice, vol. 137, pp. 173–182, 2018. View at: Publisher Site | Google Scholar
  274. X. Zhao, G. Liu, H. Shen et al., “Liraglutide inhibits autophagy and apoptosis induced by high glucose through GLP-1R in renal tubular epithelial cells,” International Journal of Molecular Medicine, vol. 35, no. 3, pp. 684–692, 2015. View at: Publisher Site | Google Scholar
  275. H. Hendarto, T. Inoguchi, Y. Maeda et al., “GLP-1 analog liraglutide protects against oxidative stress and albuminuria in streptozotocin-induced diabetic rats via protein kinase A-mediated inhibition of renal NAD(P)H oxidases,” Metabolism, vol. 61, no. 10, pp. 1422–1434, 2012. View at: Publisher Site | Google Scholar
  276. C. Marques, A. Goncalves, P. M. R. Pereira et al., “The dipeptidyl peptidase 4 inhibitor sitagliptin improves oxidative stress and ameliorates glomerular lesions in a rat model of type 1 diabetes,” Life Sciences, vol. 234, p. 116738, 2019. View at: Publisher Site | Google Scholar
  277. J. Hodrea, D. B. Balogh, A. Hosszu et al., “ReducedO-GlcNAcylation and tubular hypoxia contribute to the antifibrotic effect of SGLT2 inhibitor dapagliflozin in the diabetic kidney,” American Journal of Physiology. Renal Physiology, vol. 318, no. 4, pp. F1017–F1029, 2020. View at: Publisher Site | Google Scholar
  278. D. Yao, S. Wang, M. Wang, and W. Lu, “Renoprotection of dapagliflozin in human renal proximal tubular cells via the inhibition of the high mobility group box 1receptor for advanced glycation end products nuclear factor kappaB signaling pathway,” Molecular Medicine Reports, vol. 18, pp. 3625–3630, 2018. View at: Google Scholar
  279. H. J. L. Heerspink, P. Perco, S. Mulder et al., “Canagliflozin reduces inflammation and fibrosis biomarkers: a potential mechanism of action for beneficial effects of SGLT2 inhibitors in diabetic kidney disease,” Diabetologia, vol. 62, no. 7, pp. 1154–1166, 2019. View at: Publisher Site | Google Scholar
  280. S. Tanaka, Y. Sugiura, H. Saito et al., “Sodium-glucose cotransporter 2 inhibition normalizes glucose metabolism and suppresses oxidative stress in the kidneys of diabetic mice,” Kidney International, vol. 94, no. 5, pp. 912–925, 2018. View at: Publisher Site | Google Scholar
  281. A. Ojima, T. Matsui, Y. Nishino, N. Nakamura, and S. Yamagishi, “Empagliflozin, an inhibitor of sodium-glucose cotransporter 2 exerts anti-inflammatory and antifibrotic effects on experimental diabetic nephropathy partly by suppressing AGEs-receptor axis,” Hormone and Metabolic Research, vol. 47, pp. 686–692, 2015. View at: Google Scholar
  282. X. Xu, P. Chen, Q. Zheng, Y. Wang, and W. Chen, “Effect of pioglitazone on diabetic nephropathy and expression of HIF-1α and VEGF in the renal tissues of type 2 diabetic rats,” Diabetes Research and Clinical Practice, vol. 93, no. 1, pp. 63–69, 2011. View at: Publisher Site | Google Scholar

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