Oxidative Stress in Disease and Aging: Mechanisms and Therapies 2016View this Special Issue
Review Article | Open Access
Role of NADPH Oxidase in Metabolic Disease-Related Renal Injury: An Update
Metabolic syndrome has been linked to an increased risk of chronic kidney disease. The underlying pathogenesis of metabolic disease-related renal injury remains obscure. Accumulating evidence has shown that NADPH oxidase is a major source of intrarenal oxidative stress and is upregulated by metabolic factors leading to overproduction of ROS in podocytes, endothelial cells, and mesangial cells in glomeruli, which is closely associated with the initiation and progression of glomerular diseases. This review focuses on the role of NADPH oxidase-induced oxidative stress in the pathogenesis of metabolic disease-related renal injury. Understanding of the mechanism may help find potential therapeutic strategies.
Metabolic syndrome is a constellation of interconnected risk factors for cardiovascular diseases and type 2 diabetes, including dyslipidemia, hypertension, hyperglycemia, abdominal obesity, and insulin resistance [1, 2]. Along with cardiovascular diseases and type 2 diabetes, accumulating evidence shows that metabolic syndrome contributes to an increased risk of microalbuminuria and/or chronic kidney disease (CKD) [3–7]. However, it remains unclear whether there is a definitive cause-and-effect relationship between metabolic syndrome and renal injury.
Research on the underlying pathogenesis of metabolic disease-related renal injury has suggested an important role of oxidative stress, which is a result of reactive oxygen species (ROS) overproduction, mitochondrial dysfunction, and/or impaired antioxidant system . There are numerous intrarenal sources of ROS, such as mitochondrial electron transport chain, xanthine oxidase, and uncoupled nitric oxide (NO) synthase, while nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is generally accepted as the major producer [9–13].
NADPH oxidases are multisubunit enzymes composing membrane and cytosolic components that transfer electrons across biological membranes. There are seven members in the Nox family of NADPH oxidase, including Nox1–Nox5 and dual oxidases, Duox1 and Duox2, with different activation mechanisms and tissue distribution [13–16]. The Nox homologues are widely expressed throughout the kidney. Nox1, Nox2, Nox4, and Nox5 are predominantly expressed in glomerular endothelial cells, tubulointerstitial cells, and glomerular cells, that is, mesangial cells and glomerular epithelial cells . Various homologue-specific mechanisms regulate the activity of the Nox family involving a complex series of protein/protein interactions, phosphorylation and translocation of its subunits, and Rac activation. Numerous stimuli and agonists like transforming growth factor-β (TGF-β), angiotensin II (Ang II), hyperglycemia, oxidized low density lipoprotein (oxLDL), insulin-like growth factor-1 (IGF-1), vascular endothelial growth factor (VEGF), and aldosterone are capable of upregulating the activity and/or the expression of NADPH oxidases, subsequently leading to overproduction of ROS including the immediate product superoxide and the following hydrogen peroxide.
The proposed functions of NADPH oxidase-derived ROS in the kidney are mainly regulation of renal blood flow, alteration of cell fate, and regulation of gene expression. Superoxide avidly reacts with nitric oxide (NO) limiting its relaxing effect on afferent arterioles and mediates the activation of inflammasome, while hydrogen peroxide is involved in the activation of protein tyrosine kinases, phospholipases, serine/threonine kinases, and so forth, resulting in enhanced epithelial-to-mesenchymal transition (EMT), apoptosis of podocytes, and promotion of cellular hypertrophy [18–25].
The present review will focus on the role of NADPH oxidase-induced oxidative stress in the pathogenesis of metabolic disease-related renal injury.
2. NADPH Oxidase and Diabetic Nephropathy
Diabetic nephropathy (DN) is the major complication of type 1 and type 2 diabetes and is one of the leading causes of end-stage renal disease (ESRD) . It is characterized by functional deficits with proteinuria and decreased glomerular filtration, as well as structural changes, such as loss of podocytes, proliferation and expansion of mesangial cells and matrix, thickening of glomerular and tubular basement membranes, tubular atrophy, interstitial fibrosis, and arteriosclerosis. Increasing evidence has demonstrated that NADPH oxidase-induced oxidative stress plays a pivotal role in the initiation and development of DN [11, 27]. Blockade of NADPH oxidase-derived ROS generation ameliorates diabetes-induced glomerular injury via reducing podocyte loss, proteinuria, glomerular hypertrophy, and mesangial matrix expansion [28–33].
Damage and depletion of podocytes due to apoptosis occur during early DN, presented as actin cytoskeleton rearrangement, podocyte foot process effacement, and slit diaphragm disruption . Studies have highlighted the role of podocytes in DN pathogenesis and revealed the upregulation of the NADPH oxidase subunits expression, predominantly Nox4 and Nox1, in type 1 diabetic OVE26 mice and type 2 diabetic db/db mice, following excessive ROS generation and podocytes apoptosis which contributes to albuminuria [20, 35–37]. In vitro studies also have shown that high glucose induced the upregulation of NADPH oxidase expression, enhancement of NADPH oxidase activity, and apoptosis induction in podocytes at later time points [35, 37–39]. Eid et al. found that the increase of Nox4 expression was attributed to the inactivation of AMP-activated protein kinase (AMPK), and Nox4 promoted podocyte apoptosis via p53- and PUMA-dependent apoptotic pathway in high glucose condition [35, 40]. Other NADPH oxidase subunits, such as Nox2, p22phox, and p67phox, are also expressed on podocytes. However, very little is known concerning the regulation of these subunits in the presence of high glucose [11, 41–43].
Besides podocyte injury, two other morphological alterations during early DN are mesangial matrix accumulation and cell hypertrophy leading to thickening of glomerular basement membrane [27, 44]. The important role of NADPH oxidase in mesangial cell injury has been demonstrated in experimental models of diabetes as well as in cultured cells exposed to high glucose, while the molecular mechanisms remain speculative. High glucose induces upregulation of Nox4 and p22phox expression in mesangial cells as well as in diabetic kidney, and Nox4 and p22phox mediate cell hypertrophy and fibronectin expression [12, 45–48]. Since p22phox interacts with Nox4 and enhances its activity, Gorin and Wauquier suggested that p22phox and Nox4 might form a complex that contributed to high glucose-dependent oxidative stress and the subsequent fibrotic processes . The role of other NADPH oxidase subunits in mesangial cell injury has been less studied and the findings are controversial.
Furthermore, NADPH oxidase also mediates the ROS generation induced by other mediators in DN such as Ang II and TGF-β [42, 49–51]. Induced by Ang II, an acute increase and prolonged upregulation of Nox4 expression both take place in mesangial cells, and Nox4 mediates ROS generation leading to activation of signalling, for instance, extracellular signal-regulated kinase-1/2 (ERK1/2) , Akt/protein kinase B (Akt/PKB) , and proline-rich tyrosine kinase-2 (Pyk-2)/Src/3-phosphoinositide-dependent protein kinase-1 (PDK-1) , which results in hypertrophy and increased fibronectin expression. Induced by TGF-β, Nox4 expression within mitochondria in podocytes is upregulated via the Sma and Mad homologue (Smad) 2/3 pathway and ultimately results in ROS overproduction, mitochondrial dysfunction, and podocyte apoptosis [53, 54].
3. NADPH Oxidase and Hyperhomocysteinemia-Associated Glomerular Injury
Hyperhomocysteinemia (hHcys) is defined as a pathological condition characterized by abnormal elevation of homocysteine (Hcys) plasma concentration and has been considered as a pivotal independent risk factor in the development of progressive glomerulosclerosis and/or ESRD [55–57]. Previous evidence has revealed that Hcys induces endothelial injury, vascular smooth muscle cells proliferation, and extracellular matrix (ECM) metabolism disturbance [58–61]. Considering the similarity of pathological alterations between Hcys-induced arterial injury and glomerular injury, the role of hHcys in glomerulosclerosis has been verified. Although the mechanism by which Hcys induces glomerular injury remains poorly understood, there is evidence that NADPH oxidase-derived oxidative stress is involved in the development of glomerular injury induced by Hcys [62–65]. An experimental model of hHcys was reported to develop glomerulosclerosis, characterized by local oxidative stress, podocyte dysfunction, mesangial expansion, and fibrosis, which could be significantly attenuated by treatment of NADPH oxidase inhibitors .
Podocyte injury is a critical early event leading to glomerulosclerosis. It has been revealed that Hcys induces podocyte damage and slit diaphragm disruption, causing proteinuria and glomerular sclerosis . Zhang et al.  found that, in mice lacking Nox2 gene, hHcys induced by folate-free diet led to less severe podocyte injury and glomerulosclerosis, as shown by attenuated foot process effacement and podocyte loss, lower proteinuria, and glomerular damage index, as well as higher glomerular filtration rate. Thus, NADPH oxidase is suggested to be essential for Hcys-induced podocyte injury and glomerulosclerosis. Furthermore, Hcys stimulation was documented to upregulate NOX2 and p47phox expression and induce their aggregation in lipid raft (LR) clusters in podocytes, while disrupting LR clustering markedly blocked the enrichment of the NADPH oxidase subunits, decreased the enzyme activity, and functionally attenuated Hcys-induced podocyte injury. These findings indicate that NADPH oxidase subunits aggregation and activation through LR clustering are important molecular mechanisms in Hcys-induced podocytes injury . Hcys is also confirmed to induce podocytes to undergo EMT and inflammasome activation through NADPH oxidase-derived oxidative stress, which consequently leads to glomerular injury and sclerosis [69–71].
Ingram’s research group and others also have clarified that Hcys induces alterations of ECM metabolism in mesangial cells, another important event leading to glomerulosclerosis and loss of renal function . Hcys was reported to upregulate tissue inhibitor of metalloproteinase-1 and induce collagen type I accumulation, accompanied by enhanced cell proliferation and NADPH oxidase activity in rat mesangial cells . Hcys-induced activation of NADPH oxidase is suggested to be mediated by enhanced ceramide synthesis and the subsequent increase of Rac GTPase activity . There is also evidence showing that the N-methyl-D-aspartate (NMDA) receptor may mediate activation of NADPH oxidase in hHcys-associated glomerular injury . In addition, Hcys has been found to cause mesangial apoptosis via oxidative stress and p38-mitogen-activated protein kinase activation, thereby suggesting another underlying mechanism of hHcys-associated glomerular injury .
4. NADPH Oxidase and Hyperlipidemia-Associated Glomerular Injury
The concern of the association between hyperlipidemia and renal diseases may date back to the 19th century. Since then, accumulating evidence in experimental findings and clinical observations has suggested an important role of hyperlipidemia in the progression of glomerulosclerosis [76–81]. Hyperlipidemia-associated glomerular injury is mainly characterized by lipid or lipoprotein deposition, macrophage infiltration, and mesangial expansion. As with other metabolic factors, such as hyperglycemia and hHcys, oxidative stress is proved to contribute to the deleterious effects of hyperlipidemia on renal injury. In high-fat diet fed mice, the expression of NADPH oxidase subunits, including p47phox, Nox2, and p67phox, was significantly upregulated, and the inhibitor could ameliorate hyperlipidemia-induced endothelial dysfunction via inhibition of NADPH oxidase expression . However, in the study of Scheuer et al., it is reported that xanthine oxidoreductase rather than NADPH oxidase mainly accounted for the generation of ROS in glomeruli and tubulointerstitium induced by hyperlipidemia . In addition, Joles et al. clarified that both hypercholesterolemia and hypertriglyceridemia aggravated renal injury predominantly via podocytes, accompanied by activation and injury of tubulointerstitial cells, lacking evidence of mesangial activation, proliferation, or matrix accumulation . Furthermore, hyperlipidemia often coexists with other metabolic syndrome components and accelerates the progression of glomerular injury together [84, 85].
5. NADPH Oxidase and Hyperuricemia-Related Kidney Disease
Uric acid (UA) is an intermediate product in the purine degradation pathway in cells but is the final product of purine catabolism in humans, due to the loss of uricase activity during hominoid evolution . The role of UA in CKD remains controversial, and the “UA debate” has been going on for decades . UA has been considered as a major antioxidant in protecting cells from oxidative injury proved by abundant experimental and clinical evidence . On the other hand, epidemiologic evidence and experimental models also have shown that hyperuricemia may impose detrimental effects as a prooxidant [89–92]. UA is often associated with other risk factors of CKD, including diabetes, hypertension, and inflammation , which makes it difficult to dissect the role of UA itself in the progression of CKD. However, a recent study showed an association between hyperuricemia and renal damage independently of hypertension and intrarenal renin-angiotensin system (RAS) activation .
In the past, hyperuricemia was thought to cause kidney disease by a crystal-dependent mechanism. The crystal of monosodium urate may induce potassium efflux, lysosomal rupture, and mitochondrial ROS production, which provoke inflammasome and induce the secretion of proinflammatory cytokines, eventually causing inflammation and renal injury. The crystal-independent mechanism of hyperuricemia-related kidney disease remains poorly understood. The main pathophysiological mechanisms of hyperuricemia-related kidney disease include endothelial dysfunction, activation of local RAS, oxidative stress, and proinflammatory and proliferative effects. NADPH oxidase is suggested to play a role in the pathogenesis of hyperuricemia-related kidney disease, as with other metabolic disease-related renal injuries. It has been revealed that hyperuricemia is associated with endothelial dysfunction, due to oxidative stress with activation of RAS and a decrease of NO bioavailability [95, 96]. In an experimental model of hyperuricemia, enhanced intrarenal oxidative stress, increased expression of NOX-4 and Ang II, and decreased NO bioavailability were observed . The aging and apoptosis of endothelial cells induced by hyperuricemia were ameliorated by antioxidants . Furthermore, there is evidence that mitochondrial alterations and decreased intracellular ATP are implicated in UA-induced endothelial dysfunction . In cultured renal tubular cells, it has been shown that UA induces EMT and apoptosis of renal tubular cells which is ameliorated by antioxidants, suggesting a detrimental role of oxidative stress .
6. NADPH Oxidase and Obesity-Related Kidney Disease
Oxidative stress is also associated with other metabolic kidney diseases such as obesity-related kidney disease . It is well documented that the glomerular scarring in obesity-associated focal segmental glomerulosclerosis is driven by podocyte injury, which may partly be a result of the NADPH oxidase-derived oxidative stress induced by upregulated Ang II and TGF-β . There is supplemental data supporting the fact that NADPH oxidase-mediated oxidative injury to the proximal tubule contributes to proteinuria in obese rats . In addition, oxidative stress is demonstrated to play a role in the pathogenesis of renal injury through its contribution to progressive vascular dysfunction and remodeling [104, 105]. Collectively, NADPH oxidase-derived oxidative stress is suggested to trigger the progression of obesity-related kidney disease.
The NADPH oxidase is widely expressed throughout the kidney and is a major source of intrarenal oxidative stress. Metabolic stimuli elicit the upregulation of NADPH oxidase expression and the enhancement of NADPH oxidase activity. As depicted in Figure 1, ROS generated by NADPH oxidase plays a pivotal role in the pathogenesis of glomerular diseases related to metabolic diseases. Hence, approaches to reduce oxidative stress by antioxidants may be potential therapies to prevent and treat metabolic disease-related renal injury.
The authors declare that they have no competing interests.
This work was supported by grants from the National Natural Science Foundation of China (no. 81170662, no. 31200872, no. 81470964, no. 81570671, and no. 81522010), a grant from Wuhan Science and Technology Bureau (no. 2015060101010039), and Specialized Research Fund for the Doctoral Program of Higher Education of China (no. 20130142110064).
- E. Kassi, P. Pervanidou, G. Kaltsas, and G. Chrousos, “Metabolic syndrome: definitions and controversies,” BMC Medicine, vol. 9, article 48, 2011.
- K. G. M. M. Alberti, P. Zimmet, and J. Shaw, “The metabolic syndrome—a new worldwide definition,” The Lancet, vol. 366, no. 9491, pp. 1059–1062, 2005.
- J. Chen, P. Muntner, L. L. Hamm et al., “The metabolic syndrome and chronic kidney disease in U.S. Adults,” Annals of Internal Medicine, vol. 140, no. 3, pp. 167–174, 2004.
- M. Kurella, J. C. Lo, and G. M. Chertow, “Metabolic syndrome and the risk for chronic kidney disease among nondiabetic adults,” Journal of the American Society of Nephrology, vol. 16, no. 7, pp. 2134–2140, 2005.
- J. Chen, P. Muntner, L. L. Hamm et al., “Insulin resistance and risk of chronic kidney disease in nondiabetic US adults,” Journal of the American Society of Nephrology, vol. 14, no. 2, pp. 469–477, 2003.
- J. Chen, D. Gu, C.-S. Chen et al., “Association between the metabolic syndrome and chronic kidney disease in Chinese adults,” Nephrology Dialysis Transplantation, vol. 22, no. 4, pp. 1100–1106, 2007.
- C. M. Hoehner, K. J. Greenlund, S. Rith-Najarian, M. L. Casper, and W. M. McClellan, “Association of the insulin resistance syndrome and microalbuminuria among nondiabetic native Americans. The Inter-Tribal Heart Project,” Journal of the American Society of Nephrology, vol. 13, no. 6, pp. 1626–1634, 2002.
- M. Nita and A. Grzybowski, “The role of the reactive oxygen species and oxidative stress in the pathomechanism of the age-related ocular diseases and other pathologies of the anterior and posterior eye segments in adults,” Oxidative Medicine and Cellular Longevity, vol. 2016, Article ID 3164734, 23 pages, 2016.
- Y. Gorin and K. Block, “Nox as a target for diabetic complications,” Clinical Science, vol. 125, no. 8, pp. 361–382, 2013.
- P. S. Gill and C. S. Wilcox, “NADPH oxidases in the kidney,” Antioxidants and Redox Signaling, vol. 8, no. 9-10, pp. 1597–1607, 2006.
- Y. Gorin and K. Block, “Nox4 and diabetic nephropathy: with a friend like this, who needs enemies?” Free Radical Biology and Medicine, vol. 61, pp. 130–142, 2013.
- Y. Gorin, K. Block, J. Hernandez et al., “Nox4 NAD(P)H oxidase mediates hypertrophy and fibronectin expression in the diabetic kidney,” Journal of Biological Chemistry, vol. 280, no. 47, pp. 39616–39626, 2005.
- Y. Gorin and F. Wauquier, “Upstream regulators and downstream effectors of NADPH oxidases as novel therapeutic targets for diabetic kidney disease,” Molecules and Cells, vol. 38, no. 4, pp. 285–296, 2015.
- K. Bedard and K.-H. Krause, “The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology,” Physiological Reviews, vol. 87, no. 1, pp. 245–313, 2007.
- A. Panday, M. K. Sahoo, D. Osorio, and S. Batra, “NADPH oxidases: an overview from structure to innate immunity-associated pathologies,” Cellular and Molecular Immunology, vol. 12, no. 1, pp. 5–23, 2015.
- S. Chen, X.-F. Meng, and C. Zhang, “Role of NADPH oxidase-mediated reactive oxygen species in podocyte injury,” BioMed Research International, vol. 2013, Article ID 839761, 7 pages, 2013.
- S. A. Jones, J. T. Hancock, O. T. G. Jones, A. Neubauer, and N. Topley, “The expression of NADPH oxidase components in human glomerular mesangial cells: detection of protein and mRNA for p47phox, p67phox, and p22phox,” Journal of the American Society of Nephrology, vol. 5, no. 7, pp. 1483–1491, 1995.
- A. Whaley-Connell, J. Habibi, R. Nistala et al., “Attenuation of NADPH oxidase activation and glomerular filtration barrier remodeling with statin treatment,” Hypertension, vol. 51, no. 2, pp. 474–480, 2008.
- C. D. Bondi, N. Manickam, D. Y. Lee et al., “NAD(P)H oxidase mediates TGF-β1-induced activation of kidney myofibroblasts,” Journal of the American Society of Nephrology, vol. 21, no. 1, pp. 93–102, 2010.
- A. A. Eid, Y. Gorin, B. M. Fagg et al., “Mechanisms of podocyte injury in diabetes: role of cytochrome P450 and NADPH oxidases,” Diabetes, vol. 58, no. 5, pp. 1201–1211, 2009.
- K. Wingler, S. Wünsch, R. Kreutz, L. Rothermund, M. Paul, and H. H. H. W. Schmidt, “Upregulation of the vascular NAD(P)H-oxidase isoforms Nox1 and Nox4 by the renin-angiotensin system in vitro and in vivo,” Free Radical Biology and Medicine, vol. 31, no. 11, pp. 1456–1464, 2001.
- K. Block, A. Eid, K. K. Griendling, D.-Y. Lee, Y. Wittrant, and Y. Gorin, “Nox4 NAD(P)H oxidase mediates Src-dependent tyrosine phosphorylation of PDK-1 in response to angiotensin II: role in mesangial cell hypertrophy and fibronectin expression,” The Journal of Biological Chemistry, vol. 283, no. 35, pp. 24061–24076, 2008.
- D. Meng, D.-D. Lv, and J. Fang, “Insulin-like growth factor-I induces reactive oxygen species production and cell migration through Nox4 and Rac1 in vascular smooth muscle cells,” Cardiovascular Research, vol. 80, no. 2, pp. 299–308, 2008.
- K. Miyata, M. Rahman, T. Shokoji et al., “Aldosterone stimulates reactive oxygen species production through activation of NADPH oxidase in rat mesangial cells,” Journal of the American Society of Nephrology, vol. 16, no. 10, pp. 2906–2912, 2005.
- J. L. Barnes and Y. Gorin, “Myofibroblast differentiation during fibrosis: role of NAD(P)H oxidases,” Kidney International, vol. 79, no. 9, pp. 944–956, 2011.
- F. A. Hakim and A. Pflueger, “Role of oxidative stress in diabetic kidney disease,” Medical Science Monitor, vol. 16, no. 2, pp. RA37–RA48, 2010.
- D. K. Singh, P. Winocour, and K. Farrington, “Oxidative stress in early diabetic nephropathy: fueling the fire,” Nature Reviews Endocrinology, vol. 7, no. 3, pp. 176–184, 2011.
- K. Asaba, A. Tojo, M. L. Onozato et al., “Effects of NADPH oxidase inhibitor in diabetic nephropathy,” Kidney International, vol. 67, no. 5, pp. 1890–1898, 2005.
- S. M. Nam, M. Y. Lee, J. H. Koh et al., “Effects of NADPH oxidase inhibitor on diabetic nephropathy in OLETF rats: the role of reducing oxidative stress in its protective property,” Diabetes Research and Clinical Practice, vol. 83, no. 2, pp. 176–182, 2009.
- M. Kitada, S. Kume, N. Imaizumi, and D. Koya, “Resveratrol improves oxidative stress and protects against diabetic nephropathy through normalization of Mn-SOD dysfunction in AMPK/SIRT1- independent pathway,” Diabetes, vol. 60, no. 2, pp. 634–643, 2011.
- A. Tojo, K. Asaba, and M. L. Onozato, “Suppressing renal NADPH oxidase to treat diabetic nephropathy,” Expert Opinion on Therapeutic Targets, vol. 11, no. 8, pp. 1011–1018, 2007.
- Y. Gorin, R. C. Cavaglieri, K. Khazim et al., “Targeting NADPH oxidase with a novel dual Nox1/Nox4 inhibitor attenuates renal pathology in type 1 diabetes,” American Journal of Physiology—Renal Physiology, vol. 308, no. 11, pp. F1276–F1287, 2015.
- M. Fujii, T. Inoguchi, Y. Maeda et al., “Pitavastatin ameliorates albuminuria and renal mesangial expansion by downregulating NOX4 in db/db mice,” Kidney International, vol. 72, no. 4, pp. 473–480, 2007.
- S. J. Shankland, “The podocyte's response to injury: role in proteinuria and glomerulosclerosis,” Kidney International, vol. 69, no. 12, pp. 2131–2147, 2006.
- A. A. Eid, B. M. Ford, K. Block et al., “AMP-activated protein kinase (AMPK) negatively regulates Nox4-dependent activation of p53 and epithelial cell apoptosis in diabetes,” The Journal of Biological Chemistry, vol. 285, no. 48, pp. 37503–37512, 2010.
- L. L. Zhou, F. F. Hou, G. B. Wang et al., “Accumulation of advanced oxidation protein products induces podocyte apoptosis and deletion through NADPH-dependent mechanisms,” Kidney International, vol. 76, no. 11, pp. 1148–1160, 2009.
- K. Susztak, A. C. Raff, M. Schiffer, and E. P. Böttinger, “Glucose-induced reactive oxygen species cause apoptosis of podocytes and podocyte depletion at the onset of diabetic nephropathy,” Diabetes, vol. 55, no. 1, pp. 225–233, 2006.
- J. Xu, Z. Li, P. Xu, and Z. Yang, “Protective effects of leukemia inhibitory factor against oxidative stress during high glucose-induced apoptosis in podocytes,” Cell Stress and Chaperones, vol. 17, no. 4, pp. 485–493, 2012.
- J. Toyonaga, K. Tsuruya, H. Ikeda et al., “Spironolactone inhibits hyperglycemia-induced podocyte injury by attenuating ROS production,” Nephrology Dialysis Transplantation, vol. 26, no. 8, pp. 2475–2484, 2011.
- A. Papadimitriou, E. B. M. I. Peixoto, K. C. Silva, J. M. Lopes de Faria, and J. B. Lopes de Faria, “Increase in AMPK brought about by cocoa is renoprotective in experimental diabetes mellitus by reducing NOX4/TGFβ-1 signaling,” The Journal of Nutritional Biochemistry, vol. 25, no. 7, pp. 773–784, 2014.
- S. Greiber, T. Münzel, S. Kästner, B. Müller, P. Schollmeyer, and H. Pavenstädt, “NAD(P)H oxidase activity in cultured human podocytes: effects of adenosine triphosphate,” Kidney International, vol. 53, no. 3, pp. 654–663, 1998.
- R. Nistala, A. Whaley-Connell, and J. R. Sowers, “Redox control of renal function and hypertension,” Antioxidants & Redox Signaling, vol. 10, no. 12, pp. 2047–2089, 2008.
- T. Etoh, T. Inoguchi, M. Kakimoto et al., “Increased expression of NAD(P)H oxidase subunits, NOX4 and p22phox, in the kidney of streptozotocin-induced diabetic rats and its reversibity by interventive insulin treatment,” Diabetologia, vol. 46, no. 10, pp. 1428–1437, 2003.
- Y. S. Kanwar, L. Sun, P. Xie, F.-Y. Liu, and S. Chen, “A glimpse of various pathogenetic mechanisms of diabetic nephropathy,” Annual Review of Pathology: Mechanisms of Disease, vol. 6, pp. 395–423, 2011.
- L. Zhang, S. Pang, B. Deng et al., “High glucose induces renal mesangial cell proliferation and fibronectin expression through JNK/NF-κB/NADPH oxidase/ROS pathway, which is inhibited by resveratrol,” The International Journal of Biochemistry & Cell Biology, vol. 44, no. 4, pp. 629–638, 2012.
- L. Xia, H. Wang, H. J. Goldberg, S. Munk, I. G. Fantus, and C. I. Whiteside, “Mesangial cell NADPH oxidase upregulation in high glucose is protein kinase C dependent and required for collagen IV expression,” American Journal of Physiology—Renal Physiology, vol. 290, no. 2, pp. F345–F356, 2006.
- C. Whiteside, H. Wang, L. Xia, S. Munk, H. J. Goldberg, and I. G. Fantus, “Rosiglitazone prevents high glucose-induced vascular endothelial growth factor and collagen IV expression in cultured mesangial cells,” Experimental Diabetes Research, vol. 2009, Article ID 910783, 11 pages, 2009.
- Y. Maeda, T. Inoguchi, R. Takei et al., “Inhibition of chymase protects against diabetes-induced oxidative stress and renal dysfunction in hamsters,” American Journal of Physiology—Renal Physiology, vol. 299, no. 6, pp. F1328–F1338, 2010.
- K. N. Campbell, L. Raij, and P. Mundel, “Role of angiotensin II in the development of nephropathy and podocytopathy of diabetes,” Current Diabetes Reviews, vol. 7, no. 1, pp. 3–7, 2011.
- Y. Gorin, J. M. Ricono, N.-H. Kim, B. Bhandari, G. G. Choudhury, and H. E. Abboud, “Nox4 mediates angiotensin II-induced activation of Akt/protein kinase B in mesangial cells,” American Journal of Physiology—Renal Physiology, vol. 285, no. 2, pp. F219–F229, 2003.
- J. C. Jha, S. P. Gray, D. Barit et al., “Genetic targeting or pharmacologic inhibition of NADPH oxidase Nox4 provides renoprotection in long-term diabetic nephropathy,” Journal of the American Society of Nephrology, vol. 25, no. 6, pp. 1237–1254, 2014.
- Y. Gorin, J. M. Ricono, B. Wagner et al., “Angiotensin II-induced ERK1/ERK2 activation and protein synthesis are redox-dependent in glomerular mesangial cells,” The Biochemical Journal, vol. 381, part 1, pp. 231–239, 2004.
- L. Yu, Y. Liu, Y. Wu et al., “Smad3/Nox4-mediated mitochondrial dysfunction plays a crucial role in puromycin aminonucleoside-induced podocyte damage,” Cellular Signalling, vol. 26, no. 12, pp. 2979–2991, 2014.
- R. Das, S. Xu, X. Quan et al., “Upregulation of mitochondrial Nox4 mediates TGF-β-induced apoptosis in cultured mouse podocytes,” American Journal of Physiology—Renal Physiology, vol. 306, no. 2, pp. F155–F167, 2014.
- V. W. Dennis and K. Robinson, “Homocysteinemia and vascular disease in end-stage renal disease,” Kidney International, Supplement, vol. 50, no. 57, pp. S11–S17, 1996.
- F. Yi and P.-L. Li, “Mechanisms of homocysteine-induced glomerular injury and sclerosis,” American Journal of Nephrology, vol. 28, no. 2, pp. 254–264, 2008.
- A. Gupta and K. Robinson, “Hyperhomocysteinaemia and end stage renal disease,” Journal of Nephrology, vol. 10, no. 2, pp. 77–84, 1997.
- A. Erol, M. G. Çnar, C. Can, M. Olukman, S. Ülker, and S. Koşay, “Effect of homocysteine on nitric oxide production in coronary microvascular endothelial cells,” Endothelium: Journal of Endothelial Cell Research, vol. 14, no. 3, pp. 157–161, 2007.
- K. Chow, F. Cheung, T. T. H. Lao, and O. Karmin, “Effect of homocysteine on the production of nitric oxide in endothelial cells,” Clinical and Experimental Pharmacology & Physiology, vol. 26, no. 10, pp. 817–818, 1999.
- X. Liu, F. Luo, J. Li, W. Wu, L. Li, and H. Chen, “Homocysteine induces connective tissue growth factor expression in vascular smooth muscle cells,” Journal of Thrombosis and Haemostasis, vol. 6, no. 1, pp. 184–192, 2008.
- H. Guo, J.-D. Lee, H. Uzui et al., “Effects of heparin on the production of homocysteine-induced extracellular matrix metalloproteinase-2 in cultured rat vascular smooth muscle cells,” The Canadian Journal of Cardiology, vol. 23, no. 4, pp. 275–280, 2007.
- F. Yi, M. Xia, N. Li, C. Zhang, L. Tang, and P.-L. Li, “Contribution of guanine nucleotide exchange factor Vav2 to hyperhomocysteinemic glomerulosclerosis in rats,” Hypertension, vol. 53, no. 1, pp. 90–96, 2009.
- S. Shastry, A. J. Ingram, J. W. Scholey, and L. R. James, “Homocysteine induces mesangial cell apoptosis via activation of p38-mitogen-activated protein kinase,” Kidney International, vol. 71, no. 4, pp. 304–311, 2007.
- F. Yi, A. Y. Zhang, N. Li et al., “Inhibition of ceramide-redox signaling pathway blocks glomerular injury in hyperhomocysteinemic rats,” Kidney International, vol. 70, no. 1, pp. 88–96, 2006.
- L. Pin-Lan, Y. Fan, and L. Ningjun, “Hyperhomocysteinemia: association with renal transsulfuration and redox signaling in rats,” Clinical Chemistry and Laboratory Medicine, vol. 45, no. 12, pp. 1688–1693, 2007.
- F. Yi, E. A. Dos Santos, M. Xia, Q.-Z. Chen, P.-L. Li, and N. Li, “Podocyte injury and glomerulosclerosis in hyperhomocysteinemic rats,” American Journal of Nephrology, vol. 27, no. 3, pp. 262–268, 2007.
- C. Zhang, J.-J. Hu, M. Xia et al., “Protection of podocytes from hyperhomocysteinemia-induced injury by deletion of the gp91phox gene,” Free Radical Biology & Medicine, vol. 48, no. 8, pp. 1109–1117, 2010.
- C. Zhang, J.-J. Hu, M. Xia, K. M. Boini, C. Brimson, and P.-L. Li, “Redox signaling via lipid raft clustering in homocysteine-induced injury of podocytes,” Biochimica et Biophysica Acta—Molecular Cell Research, vol. 1803, no. 4, pp. 482–491, 2010.
- C. Zhang, M. Xia, K. M. Boini et al., “Epithelial-to-mesenchymal transition in podocytes mediated by activation of NADPH oxidase in hyperhomocysteinemia,” Pflugers Archiv European Journal of Physiology, vol. 462, no. 3, pp. 455–467, 2011.
- C.-X. Li, M. Xia, W.-Q. Han et al., “Reversal by growth hormone of homocysteine-induced epithelial-to- mesenchymal transition through membrane raft-redox signaling in podocytes,” Cellular Physiology and Biochemistry, vol. 27, no. 6, pp. 691–702, 2011.
- J. M. Abais, C. Zhang, M. Xia et al., “NADPH oxidase-mediated triggering of inflammasome activation in mouse podocytes and glomeruli during hyperhomocysteinemia,” Antioxidants and Redox Signaling, vol. 18, no. 13, pp. 1537–1548, 2013.
- A. J. Ingram, J. C. Krepinsky, L. James et al., “Activation of mesangial cell MAPK in response to homocysteine,” Kidney International, vol. 66, no. 2, pp. 733–745, 2004.
- Z.-Z. Yang and A.-P. Zou, “Homocysteine enhances TIMP-1 expression and cell proliferation associated with NADH oxidase in rat mesangial cells,” Kidney International, vol. 63, no. 3, pp. 1012–1020, 2003.
- F. Yi, A. Y. Zhang, J. L. Janscha, P.-L. Li, and A.-P. Zou, “Homocysteine activates NADH/NADPH oxidase through ceramide-stimulated Rac GTPase activity in rat mesangial cells,” Kidney International, vol. 66, no. 5, pp. 1977–1987, 2004.
- C. Zhang, F. M. Yi, M. Xia et al., “NMDA receptor-mediated activation of NADPH oxidase and glomerulosclerosis in hyperhomocysteinemic rats,” Antioxidants and Redox Signaling, vol. 13, no. 7, pp. 975–986, 2010.
- J. R. Diamond, “Hyperlipidemia of nephrosis: pathophysiologic role in progressive glomerular disease,” American Journal of Medicine, vol. 87, no. 5N, pp. 25N–29N, 1989.
- S. Anderson, A. J. King, and B. M. Brenner, “Hyperlipidemia and glomerular sclerosis: an alternative viewpoint,” The American Journal of Medicine, vol. 87, no. 5, pp. 34N–38N, 1989.
- V. S. Kamanna, D. D. Roh, and M. A. Kirschenbaum, “Hyperlipidemia and kidney disease: concepts derived from histopathology and cell biology of the glomerulus,” Histology and Histopathology, vol. 13, no. 1, pp. 169–179, 1998.
- W. F. Keane, M. P. O'Donnell, B. L. Kasiske, and P. G. Schmitz, “Lipids and the progression of renal disease,” Journal of the American Society of Nephrology, vol. 1, no. 5, pp. S69–S74, 1990.
- J. A. Joles, U. Kunter, U. Janssen et al., “Early mechanisms of renal injury in hypercholesterolemic or hypertriglyceridemic rats,” Journal of the American Society of Nephrology, vol. 11, no. 4, pp. 669–683, 2000.
- B. L. Kasiske, M. P. O'Donnell, W. J. Garvis, and W. F. Keane, “Pharmacologic treatment of hyperlipidemia reduces glomerular injury in rat 5/6 nephrectomy model of chronic renal failure,” Circulation Research, vol. 62, no. 2, pp. 367–374, 1988.
- K.-P. Shen, H.-L. Lin, W.-T. Chang et al., “Eugenosedin-A ameliorates hyperlipidemia-induced vascular endothelial dysfunction via inhibition of α1-adrenoceptor/5-HT activity and NADPH oxidase expression,” Kaohsiung Journal of Medical Sciences, vol. 30, no. 3, pp. 116–124, 2014.
- H. Scheuer, W. Gwinner, J. Hohbach et al., “Oxidant stress in hyperlipidemia-induced renal damage,” American Journal of Physiology-Renal Physiology, vol. 278, no. 1, pp. F63–F74, 2000.
- L. He, L. Hao, X. Fu, M. Huang, and R. Li, “Severe hypertriglyceridemia and hypercholesterolemia accelerating renal injury: a novel model of type 1 diabetic hamsters induced by short-term high-fat / high-cholesterol diet and low-dose streptozotocin,” BMC Nephrology, vol. 16, article 51, 2015.
- J. P. Tolins, B. G. Stone, and L. Raij, “Interactions of hypercholesterolemia and hypertension in initiation of glomerular injury,” Kidney International, vol. 41, no. 5, pp. 1254–1261, 1992.
- M. Oda, Y. Satta, O. Takenaka, and N. Takahata, “Loss of urate oxidase activity in hominoids and its evolutionary implications,” Molecular Biology and Evolution, vol. 19, no. 5, pp. 640–653, 2002.
- O. S. P. Sah and Y. X. Qing, “Associations between hyperuricemia and chronic kidney disease: a review,” Nephro-Urology Monthly, vol. 7, no. 3, Article ID e27233, 2015.
- G. K. Glantzounis, E. C. Tsimoyiannis, A. M. Kappas, and D. A. Galaris, “Uric acid and oxidative stress,” Current Pharmaceutical Design, vol. 11, no. 32, pp. 4145–4151, 2005.
- R. J. Johnson, D.-H. Kang, D. Feig et al., “Is there a pathogenetic role for uric acid in hypertension and cardiovascular and renal disease?” Hypertension, vol. 41, no. 6, pp. 1183–1190, 2003.
- L. Li, C. Yang, Y. Zhao, X. Zeng, F. Liu, and P. Fu, “Is hyperuricemia an independent risk factor for new-onset chronic kidney disease?: a systematic review and meta-analysis based on observational cohort studies,” BMC Nephrology, vol. 15, no. 1, article 122, 2014.
- A. Stack, A. J. Manolis, and E. Ritz, “Detrimental role of hyperuricemia on the cardio-reno-vascular system,” Current Medical Research and Opinion, vol. 31, supplement 2, pp. 21–26, 2015.
- D.-H. Kang and T. Nakagawa, “Uric acid and chronic renal disease: possible implication of hyperuricemia on progression of renal disease,” Seminars in Nephrology, vol. 25, no. 1, pp. 43–49, 2005.
- P. Dousdampanis, K. Trigka, C. G. Musso, and C. Fourtounas, “Hyperuricemia and chronic kidney disease: an enigma yet to be solved,” Renal Failure, vol. 36, no. 9, pp. 1351–1359, 2014.
- N. Ohashi, S. Ishigaki, S. Isobe et al., “Hyperuricaemia is associated with renal damage independently of hypertension and intrarenal renin-angiotensin system activation, as well as their circadian rhythms,” Nephrology, vol. 20, no. 11, pp. 814–819, 2015.
- W.-J. Ho, W.-P. Tsai, K.-H. Yu et al., “Association between endothelial dysfunction and hyperuricaemia,” Rheumatology, vol. 49, no. 10, pp. 1929–1934, 2010.
- M.-A. Yu, L. G. Sánchez-Lozada, R. J. Johnson, and D.-H. Kang, “Oxidative stress with an activation of the renin-angiotensin system in human vascular endothelial cells as a novel mechanism of uric acid-induced endothelial dysfunction,” Journal of Hypertension, vol. 28, no. 6, pp. 1234–1242, 2010.
- L. G. Sánchez-Lozada, V. Soto, E. Tapia et al., “Role of oxidative stress in the renal abnormalities induced by experimental hyperuricemia,” American Journal of Physiology—Renal Physiology, vol. 295, no. 4, pp. F1134–F1141, 2008.
- D.-H. Kang and S.-K. Ha, “Uric acid puzzle: dual role as anti-oxidantand pro-oxidant,” Electrolyte & Blood Pressure, vol. 12, no. 1, pp. 1–6, 2014.
- L. G. Sánchez-Lozada, M. A. Lanaspa, M. Cristóbal-García et al., “Uric acid-induced endothelial dysfunction is associated with mitochondrial alterations and decreased intracellular ATP concentrations,” Nephron - Experimental Nephrology, vol. 121, no. 3-4, pp. e71–e78, 2013.
- E.-S. Ryu, M. J. Kim, H.-S. Shin et al., “Uric acid-induced phenotypic transition of renal tubular cells as a novel mechanism of chronic kidney disease,” American Journal of Physiology—Renal Physiology, vol. 304, no. 5, pp. F471–F480, 2013.
- J. E. Quigley, A. A. Elmarakby, S. F. Knight et al., “Obesity induced renal oxidative stress contributes to renal injury in salt-sensitive hypertension,” Clinical and Experimental Pharmacology and Physiology, vol. 36, no. 7, pp. 724–728, 2009.
- S. Darouich, R. Goucha, M. H. Jaafoura, S. Zekri, H. B. Maiz, and A. Kheder, “Clinicopathological characteristics of obesity-associated focal segmental glomerulosclerosis,” Ultrastructural Pathology, vol. 35, no. 4, pp. 176–182, 2011.
- J. Habibi, M. R. Hayden, J. R. Sowers et al., “Nebivolol attenuates redox-sensitive glomerular and tubular mediated proteinuria in obese rats,” Endocrinology, vol. 152, no. 2, pp. 659–668, 2011.
- H. Cai and D. G. Harrison, “Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress,” Circulation Research, vol. 87, no. 10, pp. 840–844, 2000.
- L. M. Yung, F. P. Leung, X. Yao, Z.-Y. Chen, and Y. Huang, “Reactive oxygen species in vascular wall,” Cardiovascular and Hematological Disorders-Drug Targets, vol. 6, no. 1, pp. 1–19, 2006.
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