Accelerated Kidney Aging in Diabetes Mellitus

Table 2

Examples of potential mechanisms underlying renal benefits of drugs with antiaging effects.

Drugs	Beneficial effects	Mechanisms	In vivo	In vitro	Ref.
Resveratrol	Attenuation of renal fibrosis	Regulation of AMPK/NOX4/ROS signaling	db/db mice		[255]
Resveratrol	Renoprotection	Enhancement of hypoxia-induced autophagy via Sirt1	STZ-induced diabetic rats,	Hypoxic-condition-induced rat proximal tubular epithelial cells NRK-52e	[110]
Resveratrol	Suppression of renal inflammation and mesangial cell proliferation	Modulation on Akt/NF-𝜅B pathway	STZ-induced diabetic rats;	HG-induced rat mesangial cells	[256]
Resveratrol	Regulating oxidative stress and mitochondrial function	Modulation of the Sirt1/FoxO1 signal pathway	STZ-induced diabetic rats	HG-induced rat mesangial cells	[165, 257]
Resveratrol	Renoprotection	Extenuating the oxidative stress and downregulation of RAGE expression	STZ-induced diabetic rats		[258]
Resveratrol	Ameliorating lipotoxicity, oxidative stress, apoptosis, endothelial dysfunction; glomerular matrix expansion and inflammation	Activating the AMPK-Sirt1-PGC-1α axis and PPARα through increases in AdipoR1 and AdipoR2 expression	db/db mice	HG-induced human glomerular endothelial cells and NMS2 mesangial cells	[259, 260]
Resveratrol	Protection on podocytes	Activation of autophagy involved with miR-383-5p	db/db mice	HG-induced human podocytes	[261]
Resveratrol	Protection on mesangial cells	Negative regulation of the p38 MAPK/TGF-β1 pathway	STZ-induced diabetic rats	HG-induced rat mesangial cells	[167]
Resveratrol	Protection on podocytes	Against apoptosis by increasing autophagy via miRNA-18a-5p expression	db/db mice	HG-induced human podocytes	[262]
Resveratrol	Effect on endoplasmic reticulum stress	Reducing 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]
Resveratrol	Protection on podocytes	Reducing oxidative damage and apoptosis of podocytes via Sirt1/PGC-1α mitochondrial protection		HG-induced immortalized mouse podocytes	[164]
Resveratrol	Renoprotection and reducing albuminuria	Suppression 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 stress	Aged C57BL/6 mice		[30]
Resveratrol	Regulation on endothelial dysfunction	Modulation of Sirt1 and PPARγ	db/db mice		[166]
Metformin	Restore the insulin responsiveness of podocytes	Regulating Sirt1 and AMPK activities		HG-induced rat podocytes	[182]
Metformin	Exhibiting an anti-apoptotic impact on podocytes	Activation of AMPK and inhibition of mTOR signaling		HG-induced immortalized human podocytes	[178]
Metformin	Renoprotective effect	Increasing SOD activity and decreasing malondialdehyde level; decreasing the expression levels of TGF-β1	STZ-induced diabetic rats		[264]
Metformin	Improving diabetic tubulopathy	Increasing in PGC1α activity by modulating mitochondrial dynamics and autophagy	STZ-induced diabetic mice,	HG-induced human renal proximal tubular epithelial cell line HKC8	[188]
Metformin	Against proteinuria cytotoxicity	Suppression of Akt and mTOR activation, inhibition of EMT and apoptosis and augmentation of autophagy and ER defense response through AMPK-independent and AMPK-dependent mechanisms		Albumin-induced rat renal proximal tubular cells	[187]
Metformin	Protection on podocytes	Upregulating the renal tissue nephron expression	STZ-induced rats		[180]
Metformin	Protection on podocytes	Increases extracellular ATP concentration, leading to activation of P2 receptors and consequent modulation of the podocytes’ metabolism through AMPK and NAD(P)H oxidase		HG-induced mouse podocytes	[179]
Metformin	Alleviation of cell senescence	Downregulation of Connexin43 via activation of AMPK and the inhibition of mTOR		HG-induced primary rat glomerular mesangial cells	[189]
Metformin	Alleviation of high-glucose-induced oxidative stress	Regulating p-p38MAPK protein expression		HG-induced rat glomerular mesangial cells	[265]
Metformin	Alleviation of inflammation	Inhibits nuclear factor-κB activation and inflammatory cytokines expression including monocyte chemoattractant protein-1 (MCP-1), intercellular adhesion molecular depend on AMPK		HG-induced rat glomerular mesangial cells	[183]
Metformin	Inhibition of apoptosis and inflammatory and fibrotic reactions in tubular cells	Reducing ROS generation via suppression of RAGE expression through AMP-activated protein kinase activation		AGEs induced human proximal tubular epithelial cells	[266]
Metformin	Relieving oxidative stress, slowed down abnormal cell proliferation	Enhancing autophagy and through Sirt1/FoxO1 pathway via AMPK	STZ-induced diabetic rats;	HG-induced rat mesangial cells,	[185, 186]
Metformin	Exerting anti-inflammatory	Upregulating GLP-1R expression via AMPK	db/db mice	HG-induced rat mesangial cell line (HBZY-1)	[184]
Metformin	Attenuating hypoxia	Reducing uncoupling protein-2- (UCP2-) mediated mitochondrial proton LEAK	STZ-induced diabetic rats		[267]
Metformin	Alleviating cell senescence	Reducing p21 expression by activating AMPK.		Human embryonic kidney (HEK293) cell line	[190]
Metformin	Improving epithelial-to-mesenchymal transition	Inhibiting early growth response- (Egr-) 1; inhibiting MCP-1 expression via BMP and activin membrane-bound inhibitor- (BAMBI-) mediated inhibition of ERK1/2		TGF-β1-induced rat renal tubular epithelial cell line (NRK-52E)	[268, 269]
GLP-1	Protection of podocytes	Against apoptosis, inhibition reactive oxygen species production and proinflammatory cytokine secretion, through Sirt1 activation		HG-induced mouse podocytes	[197]
GLP-1R agonist (Exendin-4)	Against renal fibrosis	Inhibiting the transfer of extracellular vesicle miR-192		HG-induced renal tubular epithelial cells	[270]
GLP-1R agonist (Exendin-4)	Inhibiting cell proliferation and fibronectin secretion	Reversing ERK phosphorylation and enhancing expression of mTOR via AMPK		HG-induced rat mesangial cells	[271]
GLP-1 analog (liraglutide)	Against renal inflammatory and protection on endothelial cells	Inhibiting STAT3/JAK2 expression via SIRT1	db/db mice	AGEs- or HG-induced endothelial cells	[272]
GLP-1R analog (liraglutide)	Ameliorating early renal injury	Increasing the expression of FoxO1 mRNA and reducing renal phosphorylation levels of Akt and FoxO1 protein	STZ-induced diabetic rats		[273]
GLP-1R analog (liraglutide)	Renoprotective effect	Inhibiting autophagy and apoptosis dependent on GLP-1R		HG-induced human renal tubular epithelial cell line (HK-2)	[274]
GLP-1 analog (liraglutide)	Against oxidative stress and albuminuria	Via a PKA-mediated inhibition of renal NAD(P)H oxidase	STZ-induced diabetic rats	HG-induced human mesangial cells	[275]
DPP 4 inhibitor (sitagliptin)	Attenuation of glomerular lesions	Alleviation of oxidative injury	STZ-induced diabetic rats		[276]
SGLT2i (dapagliflozin)	Attenuation of renal fibrosis	Elevating O-GlcNAcylation and tubular hypoxia	STZ-induced diabetic rats	HG-induced human proximal tubular epithelial cell line (HK-2)	[277]
SGLT2i (dapagliflozin)	Against inflammation and postponing the progression of renal injury	Inhibition of HMGB1-RAGE-NF-κB signaling pathway		HG-induced human proximal tubular epithelial cell line (HK-2)	[278]
SGLT2i (canagliflozin)	Against renal inflammation, extracellular matrix turnover and fibrosis	Reduction in TNFR1, IL-6, MMP7 and FN1		HG-induced human proximal tubular epithelial cell line (HK-2)	[279]
SGLT2i (Ipragliflozin)	Improvements in glomerular damage	Normalizing the levels of accumulated tricarboxylic acid cycle intermediates and increased oxidative stress	db/db mice		[280]
SGLT2i (Empagliflozin)	Anti-inflammatory and antifibrotic effects	Suppressing AGE-RAGE axis	STZ-induced diabetic rats		[281]
Pioglitazone	Reprotection in DM	Decreasing expression of hypoxia-inducible factor-1a (HIF-1a) and vascular endothelial growth factor (VEGF)	STZ-induced diabetic rats		[282]
Pioglitazone	Ameliorating aging-related renal injury	Increasing klotho, decreasing oxidative stress, and mitochondrial injury; regulating p66^Shc phosphorylation, which integrates many signaling pathways that affect mitochondrial function and longevity, by reducing protein kinase C	Aging male Sprague-Dawley rats		[201]
Dasatinib and quercetin	Decreasing human senescent cell burden	Alleviating adipose tissue senescent cell burden, decreasing skin epidermal p16^INK4A+ and p21^CIP1+ cells and circulating SASP factors in patients with DN	Human 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.