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Oxidative stress in early diabetic nephropathy: fueling the fire

Nature Reviews Endocrinology volume 7, pages 176–184 (2011)Cite this article

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Abstract

Diabetic nephropathy is a major microvascular complication of diabetes mellitus and the most common cause of end-stage renal disease worldwide. The treatment costs of diabetes mellitus and its complications represent a huge burden on health-care expenditures, creating a major need to identify modifiable factors concerned in the pathogenesis and progression of diabetic nephropathy. Chronic hyperglycemia remains the primary cause of the metabolic, biochemical and vascular abnormalities in diabetic nephropathy. Promotion of excessive oxidative stress in the vascular and cellular milieu results in endothelial cell dysfunction, which is one of the earliest and most pivotal metabolic consequences of chronic hyperglycemia. These derangements are caused by excessive production of advanced glycation end products and free radicals and by the subjugation of antioxidants and antioxidant mechanisms. An increased understanding of the role of oxidative stress in diabetic nephropathy has lead to the exploration of a number of therapeutic strategies, the success of which has so far been limited. However, judicious and timely use of current therapies to maintain good glycemic control, adequate blood pressure and lipid levels, along with lifestyle measures such as regular exercise, optimization of diet and smoking cessation, may help to reduce oxidative stress and endothelial cell dysfunction and retard the progression of diabetic nephropathy until more definitive therapies become available.

Key Points

  • Oxidative stress, which precedes the development of endothelial cell dysfunction, plays a key part in the pathogenesis of diabetic nephropathy

  • Chronic hyperglycemia is central to excessive generation of reactive oxygen species and the resultant impairment of the antioxidant response

  • No target-specific antioxidant agent is currently available, although several potential agents are under evaluation

  • Judicious use of current therapies such as antihyperglycemics, antihypertensives and statins, along with lifestyle modification, may help to contain oxidative stress in diabetes mellitus, pending the arrival of definitive therapies

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Figure 1: Endothelium-derived vasodilators and vasoconstrictors in health (left) and in diabetes mellitus (right).
Figure 2: Pathogenesis of oxidative stress in diabetes mellitus.
Figure 3: Reactive oxygen and reactive nitrogen species.
Figure 4: Glucotoxicity pathways in diabetic nephropathy.
Figure 5: Effects of oxidative stress in early diabetic nephropathy.

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References

  1. Hakim, F. A. & Pflueger, A. Role of oxidative stress in diabetic kidney disease. Med. Sci. Monit. 16, RA37–RA48 (2010).

    CAS  PubMed  Google Scholar 

  2. Foley, R. N. et al. Cardiac disease in diabetic end-stage renal disease. Diabetologia 40, 1307–1312 (1997).

    Article  CAS  PubMed  Google Scholar 

  3. Mogensen, C. E., Christensen, C. K. & Vittinghus, E. The stages in diabetic renal disease. With emphasis on the stage of incipient diabetic nephropathy. Diabetes 32 (Suppl. 2), 64–78 (1983).

    Article  PubMed  Google Scholar 

  4. Schalkwijk, C. G. & Stehouwer, C. D. Vascular complications in diabetes mellitus: the role of endothelial dysfunction. Clin. Sci. (Lond.) 109, 143–159 (2005).

    Article  CAS  Google Scholar 

  5. Singh, D. K., Winocour, P. & Farrington, K. Endothelial cell dysfunction, medial arterial calcification and osteoprotegerin in diabetes. Br. J. Diabetes Vasc. 71, 54–56 (2010).

    Google Scholar 

  6. Goligorsky, M. S., Chen, J. & Brodsky, S. Workshop: endothelial cell dysfunction leading to diabetic nephropathy: focus on nitric oxide. Hypertension 37, 744–748 (2001).

    Article  CAS  PubMed  Google Scholar 

  7. Stehouwer, C. D. Endothelial dysfunction in diabetic nephropathy: state of the art and potential significance for non-diabetic renal disease. Nephrol. Dial. Transplant. 19, 778–781 (2004).

    Article  PubMed  Google Scholar 

  8. Naidoo, N. P. The link between microalbuminuria, endothelial dysfunction and cardiovascular disease in diabetes. Cardiovasc. J. S. Afr. 13, 194–199 (2002).

    CAS  PubMed  Google Scholar 

  9. Yamagishi, S., Nakamura, K., Jinnouchi, Y., Takenaka, K. & Imaizumi, T. Molecular mechanisms for vascular injury in the metabolic syndrome. Drugs Exp. Clin. Res. 31, 123–129 (2005).

    CAS  PubMed  Google Scholar 

  10. Steinberg, H. O., Brechtel, G., Johnson, A., Fineberg, N. & Baron, A. D. Insulin-mediated skeletal muscle vasodilation is nitric oxide dependent. A novel action of insulin to increase nitric oxide release. J. Clin. Invest. 94, 1172–1179 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Yaqoob, M. et al. Relationship between markers of endothelial dysfunction, oxidant injury and tubular damage in patients with insulin-dependent diabetes mellitus. Clin. Sci. (Lond.) 85, 557–562 (1993).

    Article  CAS  Google Scholar 

  12. Nishikawa, T. et al. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 404, 787–790 (2000).

    Article  CAS  PubMed  Google Scholar 

  13. Brownlee, M. Biochemistry and molecular cell biology of diabetic complications. Nature 414, 813–820 (2001).

    Article  CAS  PubMed  Google Scholar 

  14. Forbes, J. M., Coughlan, M. T. & Cooper, M. E. Oxidative stress as a major culprit in kidney disease in diabetes. Diabetes 57, 1446–1454 (2008).

    Article  CAS  PubMed  Google Scholar 

  15. Cave, A. C. et al. NADPH oxidases in cardiovascular health and disease. Antioxid. Redox Signal. 8, 691–728 (2006).

    Article  CAS  PubMed  Google Scholar 

  16. Griendling, K. K., Minieri, C. A., Ollerenshaw, J. D. & Alexander, R. W. Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. Circ. Res. 74, 1141–1148 (1994).

    Article  CAS  PubMed  Google Scholar 

  17. Thomas, S. R., Witting, P. K. & Drummond, G. R. Redox control of endothelial function and dysfunction: molecular mechanisms and therapeutic opportunities. Antioxid. Redox Signal. 10, 1713–1765 (2008).

    Article  CAS  PubMed  Google Scholar 

  18. Li, J. M. & Shah, A. M. ROS generation by nonphagocytic NADPH oxidase: potential relevance in diabetic nephropathy. J. Am. Soc. Nephrol. 14 (Suppl. 3), S221–S226 (2003).

    Article  CAS  PubMed  Google Scholar 

  19. Geiszt, M. & Leto, T. L. The Nox family of NAD(P)H oxidases: host defense and beyond. J. Biol. Chem. 279, 51715–51718 (2004).

    Article  CAS  PubMed  Google Scholar 

  20. Gorin, Y. et al. Nox4 NAD(P)H oxidase mediates hypertrophy and fibronectin expression in the diabetic kidney. J. Biol. Chem. 280, 39616–39626 (2005).

    Article  CAS  PubMed  Google Scholar 

  21. Block, K., Gorin, Y. & Abboud, H. E. Subcellular localization of Nox4 and regulation in diabetes. Proc. Natl Acad. Sci. USA 106, 14385–14390 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Bucala, R. & Vlassara, H. Advanced glycosylation end products in diabetic renal and vascular disease. Am. J. Kidney Dis. 26, 875–888 (1995).

    Article  CAS  PubMed  Google Scholar 

  23. Fu, M. X. et al. Glycation, glycoxidation, and cross-linking of collagen by glucose. Kinetics, mechanisms, and inhibition of late stages of the Maillard reaction. Diabetes 43, 676–683 (1994).

    Article  CAS  PubMed  Google Scholar 

  24. Simm, A. et al. Advanced glycation endproducts stimulate the MAP-kinase pathway in tubulus cell line LLC-PK1. FEBS Lett. 410, 481–484 (1997).

    Article  CAS  PubMed  Google Scholar 

  25. Gugliucci, A. & Bendayan, M. Renal fate of circulating advanced glycated end products (AGE): evidence for reabsorption and catabolism of AGE-peptides by renal proximal tubular cells. Diabetologia 39, 149–160 (1996).

    Article  CAS  PubMed  Google Scholar 

  26. Coughlan, M. T. et al. RAGE-induced cytosolic ROS promote mitochondrial superoxide generation in diabetes. J. Am. Soc. Nephrol. 20, 742–752 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Kiritoshi, S. et al. Reactive oxygen species from mitochondria induce cyclooxygenase-2 gene expression in human mesangial cells: potential role in diabetic nephropathy. Diabetes 52, 2570–2577 (2003).

    Article  CAS  PubMed  Google Scholar 

  28. Gibb, D. M. et al. Renal tubular proteinuria and microalbuminuria in diabetic patients. Arch. Dis. Child. 64, 129–134 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Pflueger, A. C., Osswald, H. & Knox, F. G. Adenosine-induced renal vasoconstriction in diabetes mellitus rats: role of nitric oxide. Am. J. Physiol. 276, F340–F346 (1999).

    CAS  PubMed  Google Scholar 

  30. Balakumar, P., Chakkarwar, V. A., Krishnan, P. & Singh, M. Vascular endothelial dysfunction: a tug of war in diabetic nephropathy? Biomed. Pharmacother. 63, 171–179 (2009).

    Article  CAS  PubMed  Google Scholar 

  31. MacNaul, K. L. & Hutchinson, N. I. Differential expression of iNOS and cNOS mRNA in human vascular smooth muscle cells and endothelial cells under normal and inflammatory conditions. Biochem. Biophys. Res. Commun. 196, 1330–1334 (1993).

    Article  CAS  PubMed  Google Scholar 

  32. Buerk, D. G. Can we model nitric oxide biotransport? A survey of mathematical models for a simple diatomic molecule with surprisingly complex biological activities. Annu. Rev. Biomed. Eng. 3, 109–143 (2001).

    Article  CAS  PubMed  Google Scholar 

  33. Palm, F. Intrarenal oxygen in diabetes and a possible link to diabetic nephropathy. Clin. Exp. Pharmacol. Physiol. 33, 997–1001 (2006).

    Article  CAS  PubMed  Google Scholar 

  34. Heilig, C. W. et al. Overexpression of glucose transporters in rat mesangial cells cultured in a normal glucose milieu mimics the diabetic phenotype. J. Clin. Invest. 96, 1802–1814 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Pacher, P., Obrosova, I. G., Mabley, J. G. & Szabó, C. Role of nitrosative stress and peroxynitrite in the pathogenesis of diabetic complications. Emerging new therapeutical strategies. Curr. Med. Chem. 12, 267–275 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Shiose, A. et al. A novel superoxide-producing NAD(P)H oxidase in kidney. J. Biol. Chem. 276, 1417–1423 (2001).

    Article  CAS  PubMed  Google Scholar 

  37. Chabrashvili, T. et al. Expression and cellular localization of classic NADPH oxidase subunits in the spontaneously hypertensive rat kidney. 39, 269–274 (2002).

  38. Inoguchi, T. et al. High glucose level and free fatty acid stimulate reactive oxygen species production through protein kinase C--dependent activation of NAD(P)H oxidase in cultured vascular cells. Diabetes 49, 1939–1945 (2000).

    Article  CAS  PubMed  Google Scholar 

  39. Pautz, A. et al. Cross-talk between nitric oxide and superoxide determines ceramide formation and apoptosis in glomerular cells. Kidney Int. 61, 790–796 (2002).

    Article  CAS  PubMed  Google Scholar 

  40. Wolf, G., Reinking, R., Zahner, G., Stahl, R. A. & Shankland, S. J. Erk 1,2 phosphorylates p27(Kip1): Functional evidence for a role in high glucose-induced hypertrophy of mesangial cells. Diabetologia 46, 1090–1099 (2003).

    Article  CAS  PubMed  Google Scholar 

  41. Kim, Y. et al. Differential expression of basement membrane collagen chains in diabetic nephropathy. Am. J. Pathol. 138, 413–420 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Scivittaro, V., Ganz, M. B. & Weiss, M. F. AGEs induce oxidative stress and activate protein kinase C-beta(II) in neonatal mesangial cells. Am. J. Physiol. Renal Physiol. 278, F676–F683 (2000).

    Article  CAS  PubMed  Google Scholar 

  43. Lander, H. M. et al. Activation of the receptor for advanced glycation end products triggers a p21(ras)-dependent mitogen-activated protein kinase pathway regulated by oxidant stress. J. Biol. Chem. 272, 17810–17814 (1997).

    Article  CAS  PubMed  Google Scholar 

  44. Simon, A. R., Rai, U., Fanburg, B. L. & Cochran, B. H. Activation of the JAK-STAT pathway by reactive oxygen species. Am. J. Physiol. 275, C1640–C1652 (1998).

    Article  CAS  PubMed  Google Scholar 

  45. Mason, R. M. & Wahab, N. A. Extracellular matrix metabolism in diabetic nephropathy. J. Am. Soc. Nephrol. 14, 1358–1373 (2003).

    Article  CAS  PubMed  Google Scholar 

  46. Palmer, H. J. & Paulson, K. E. Reactive oxygen species and antioxidants in signal transduction and gene expression. Nutr. Rev. 55, 353–361 (1997).

    Article  CAS  PubMed  Google Scholar 

  47. Nath, K. A. et al. Redox regulation of renal DNA synthesis, transforming growth factor-beta1 and collagen gene expression. Kidney Int. 53, 367–381 (1998).

    Article  CAS  PubMed  Google Scholar 

  48. Park, S. K. et al. Hydrogen peroxide is a novel inducer of connective tissue growth factor. Biochem. Biophys. Res. Commun. 284, 966–971 (2001).

    Article  CAS  PubMed  Google Scholar 

  49. Spurney, R. F. & Coffman, T. M. Stressed-out podocytes in diabetes? J. Am. Soc. Nephrol. 19, 2035–2037 (2008).

    Article  PubMed  Google Scholar 

  50. Susztak, K., Raff, A. C., Schiffer, M. & Böttinger, E. P. Glucose-induced reactive oxygen species cause apoptosis of podocytes and podocyte depletion at the onset of diabetic nephropathy. Diabetes 55, 225–233 (2006).

    Article  CAS  PubMed  Google Scholar 

  51. Zheng, S. et al. Podocyte-specific overexpression of the antioxidant metallothionein reduces diabetic nephropathy. J. Am. Soc. Nephrol. 19, 2077–2085 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Allen, D. A., Harwood, S., Varagunam, M., Raftery, M. J. & Yaqoob, M. M. High glucose-induced oxidative stress causes apoptosis in proximal tubular epithelial cells and is mediated by multiple caspases. FASEB J. 17, 908–910 (2003).

    Article  CAS  PubMed  Google Scholar 

  53. Baricos, W. H., Cortez, S. L., Deboisblanc, M. & Xin, S. Transforming growth factor-beta is a potent inhibitor of extracellular matrix degradation by cultured human mesangial cells. J. Am. Soc. Nephrol. 10, 790–795 (1999).

    CAS  PubMed  Google Scholar 

  54. Lee, H. B., Yu, M. R., Yang, Y., Jiang, Z. & Ha, H. Reactive oxygen species-regulated signaling pathways in diabetic nephropathy. J. Am. Soc. Nephrol. 14 (Suppl. 3), S241–S245 (2003).

    Article  CAS  PubMed  Google Scholar 

  55. Singh, D. K., Winocour, P. & Farrington, K. Mechanisms of disease: the hypoxic tubular hypothesis of diabetic nephropathy. Nat. Clin. Pract. Nephrol. 4, 216–226 (2008).

    Article  CAS  PubMed  Google Scholar 

  56. Palm, F. et al. Reduced nitric oxide in diabetic kidneys due to increased hepatic arginine metabolism: implications for renomedullary oxygen availability. Am. J. Physiol. Renal Physiol. 294, F30–F37 (2008).

    Article  CAS  PubMed  Google Scholar 

  57. Higgins, D. F. et al. Hypoxic induction of Ctgf is directly mediated by Hif-1. Am. J. Physiol. Renal Physiol. 287, F1223–F1232 (2004).

    Article  CAS  PubMed  Google Scholar 

  58. Catrina, S. B., Okamoto, K., Pereira, T., Brismar, K. & Poellinger, L. Hyperglycemia regulates hypoxia-inducible factor-1alpha protein stability and function. Diabetes 53, 3226–3232 (2004).

    Article  CAS  PubMed  Google Scholar 

  59. Callapina, M., Zhou, J., Schmid, T., Köhl, R. & Brüne, B. NO restores HIF-1alpha hydroxylation during hypoxia: role of reactive oxygen species. Free Radic. Biol. Med. 39, 925–936 (2005).

    Article  CAS  PubMed  Google Scholar 

  60. Gupte, S. A. & Wolin, M. S. Oxidant and redox signaling in vascular oxygen sensing: implications for systemic and pulmonary hypertension. Antioxid. Redox Signal. 10, 1137–1152 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Corretti, M. C. et al. Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force. J. Am. Coll. Cardiol. 39, 257–265 (2002).

    Article  PubMed  Google Scholar 

  62. Vincent, M. A., Barrett, E. J., Lindner, J. R., Clark, M. G. & Rattigan, S. Inhibiting NOS blocks microvascular recruitment and blunts muscle glucose uptake in response to insulin. Am. J. Physiol. Endocrinol. Metab. 285, E123–E129 (2003).

    Article  CAS  PubMed  Google Scholar 

  63. Stephens, J. W., Khanolkar, M. P. & Bain, S. C. The biological relevance and measurement of plasma markers of oxidative stress in diabetes and cardiovascular disease. Atherosclerosis 202, 321–329 (2009).

    Article  CAS  PubMed  Google Scholar 

  64. Wagener, F. A., Dekker, D., Berden, J. H., Scharstuhl, A. & van der Vlag, J. The role of reactive oxygen species in apoptosis of the diabetic kidney. Apoptosis 14, 1451–1458 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Bagby, S. P. Diabetic nephropathy and proximal tubule ROS: challenging our glomerulocentricity. Kidney Int. 71, 1199–1202 (2007).

    Article  CAS  PubMed  Google Scholar 

  66. Fujita, H. et al. Reduction of renal superoxide dismutase in progressive diabetic nephropathy. J. Am. Soc. Nephrol. 20, 1303–1313 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Samuni, A. M., DeGraff, W., Krishna, M. C. & Mitchell, J. B. Cellular sites of H2O2-induced damage and their protection by nitroxides. Biochim. Biophys. Acta 1525, 70–76 (2001).

    Article  CAS  PubMed  Google Scholar 

  68. Yamaguchi, T. et al. Ebselen in acute ischemic stroke: a placebo-controlled, double-blind clinical trial. Ebselen Study Group. Stroke 29, 12–17 (1998).

    Article  CAS  PubMed  Google Scholar 

  69. Chander, P. N. et al. Nephropathy in Zucker diabetic fat rat is associated with oxidative and nitrosative stress: prevention by chronic therapy with a peroxynitrite scavenger ebselen. J. Am. Soc. Nephrol. 15, 2391–2403 (2004).

    Article  CAS  PubMed  Google Scholar 

  70. Brezniceanu, M. L. et al. Attenuation of interstitial fibrosis and tubular apoptosis in db/db transgenic mice overexpressing catalase in renal proximal tubular cells. Diabetes 57, 451–459 (2008).

    Article  CAS  PubMed  Google Scholar 

  71. Abraham, N. G. & Kappas, A. Heme oxygenase and the cardiovascular-renal system. Free Radic. Biol. Med. 39, 1–25 (2005).

    Article  CAS  PubMed  Google Scholar 

  72. Kobayashi, N. et al. Critical role of bradykinin-eNOS and oxidative stress-LOX-1 pathway in cardiovascular remodeling under chronic angiotensin-converting enzyme inhibition. Atherosclerosis 187, 92–100 (2006).

    Article  CAS  PubMed  Google Scholar 

  73. Ogawa, S. et al. Angiotensin II type 1 receptor blockers reduce urinary oxidative stress markers in hypertensive diabetic nephropathy. Hypertension 47, 699–705 (2006).

    Article  CAS  PubMed  Google Scholar 

  74. Takebayashi, K., Matsumoto, S., Aso, Y. & Inukai, T. Aldosterone blockade attenuates urinary monocyte chemoattractant protein-1 and oxidative stress in patients with type 2 diabetes complicated by diabetic nephropathy. J. Clin. Endocrinol. Metab. 91, 2214–2217 (2006).

    Article  CAS  PubMed  Google Scholar 

  75. Calkin, A. C. et al. PPAR-alpha and -gamma agonists attenuate diabetic kidney disease in the apolipoprotein E knockout mouse. Nephrol. Dial. Transplant. 21, 2399–2405 (2006).

    Article  CAS  PubMed  Google Scholar 

  76. Okada, T. et al. Thiazolidinediones ameliorate diabetic nephropathy via cell cycle-dependent mechanisms. Diabetes 55, 1666–1677 (2006).

    Article  CAS  PubMed  Google Scholar 

  77. Usui, H. et al. HMG-CoA reductase inhibitor ameliorates diabetic nephropathy by its pleiotropic effects in rats. Nephrol. Dial. Transplant. 18, 265–272 (2003).

    Article  CAS  PubMed  Google Scholar 

  78. Endres, M. & Laufs, A. Effects of statins on endothelium and signaling mechanisms. Stroke 35 (Suppl. 1), 2708–2711 (2004).

    Article  CAS  PubMed  Google Scholar 

  79. Babaei-Jadidi, R., Karachalias, N., Ahmed, N., Battah, S. & Thornalley, P. J. Prevention of incipient diabetic nephropathy by high-dose thiamine and benfotiamine. Diabetes 52, 2110–2120 (2003).

    Article  CAS  PubMed  Google Scholar 

  80. Bakris, G. L. et al. Advanced glycation end-product cross-link breakers. A novel approach to cardiovascular pathologies related to the aging process. Am. J. Hypertens. 17, 23S–30S (2004).

    Article  CAS  PubMed  Google Scholar 

  81. Bolton, W. K. et al. Randomized trial of an inhibitor of formation of advanced glycation end products in diabetic nephropathy. Am. J. Nephrol. 24, 32–40 (2004).

    Article  CAS  PubMed  Google Scholar 

  82. Williams, M. E. et al. Effects of pyridoxamine in combined phase 2 studies of patients with type 1 and type 2 diabetes and overt nephropathy. Am. J. Nephrol. 27, 605–614 (2007).

    Article  CAS  PubMed  Google Scholar 

  83. Nangaku, M. et al. Anti-hypertensive agents inhibit in vivo the formation of advanced glycation end products and improve renal damage in a type 2 diabetic nephropathy rat model. J. Am. Soc. Nephrol. 14, 1212–1222 (2003).

    Article  CAS  PubMed  Google Scholar 

  84. Krone, C. A. & Ely, J. T. Ascorbic acid, glycation, glycohemoglobin and aging. Med. Hypotheses 62, 275–279 (2004).

    Article  CAS  PubMed  Google Scholar 

  85. Miyata, T. et al. Angiotensin II receptor antagonists and angiotensin-converting enzyme inhibitors lower in vitro the formation of advanced glycation end products: biochemical mechanisms. J. Am. Soc. Nephrol. 13, 2478–2487 (2002).

    Article  CAS  PubMed  Google Scholar 

  86. Gilbert, R. E. et al. Effect of ruboxistaurin on urinary transforming growth factor-beta in patients with diabetic nephropathy and type 2 diabetes. Diabetes Care 30, 995–996 (2007).

    Article  CAS  PubMed  Google Scholar 

  87. Danis, R. P. & Sheetz, M. J. Ruboxistaurin: PKC-beta inhibition for complications of diabetes. Expert Opin. Pharmacother. 10, 2913–2925 (2009).

    Article  CAS  PubMed  Google Scholar 

  88. RamachandraRao, S. P. et al. Pirfenidone is renoprotective in diabetic kidney disease. J. Am. Soc. Nephrol. 20, 1765–1775 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Miric, G. et al. Reversal of cardiac and renal fibrosis by pirfenidone and spironolactone in streptozotocin-diabetic rats. Br. J. Pharmacol. 133, 687–694 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Vanella, A. et al. L-propionyl-carnitine as superoxide scavenger, antioxidant, and DNA cleavage protector. Cell Biol. Toxicol. 16, 99–104 (2000).

    Article  CAS  PubMed  Google Scholar 

  91. Navarro, J. F. et al. Urinary protein excretion and serum tumor necrosis factor in diabetic patients with advanced renal failure: effects of pentoxifylline administration. Am. J. Kidney Dis. 33, 458–463 (1999).

    Article  CAS  PubMed  Google Scholar 

  92. Harmankaya, O., Seber, S. & Yilmaz, M. Combination of pentoxifylline with angiotensin converting enzyme inhibitors produces an additional reduction in microalbuminuria in hypertensive type 2 diabetic patients. Ren. Fail. 25, 465–470 (2003).

    Article  CAS  PubMed  Google Scholar 

  93. Russo, A. et al. Bioflavonoids as antiradicals, antioxidants and DNA cleavage protectors. Cell Biol. Toxicol. 16, 91–98 (2000).

    Article  CAS  PubMed  Google Scholar 

  94. Heitzer, T. et al. Beneficial effects of alpha-lipoic acid and ascorbic acid on endothelium-dependent, nitric oxide-mediated vasodilation in diabetic patients: relation to parameters of oxidative stress. Free Radic. Biol. Med. 31, 53–61 (2001).

    Article  CAS  PubMed  Google Scholar 

  95. Taddei, S., Virdis, A., Ghiadoni, L., Magagna, A. & Salvetti, A. Vitamin C improves endothelium-dependent vasodilation by restoring nitric oxide activity in essential hypertension. Circulation 97, 2222–2229 (1998).

    Article  CAS  PubMed  Google Scholar 

  96. Simsek, M., Naziroglu, M. & Erdinç, A. Moderate exercise with a dietary vitamin C and E combination protects against streptozotocin-induced oxidative damage to the kidney and lens in pregnant rats. Exp. Clin. Endocrinol. Diabetes 113, 53–59 (2005).

    Article  CAS  PubMed  Google Scholar 

  97. Farvid, M. S., Jalali, M., Siassi, F. & Hosseini, M. Comparison of the effects of vitamins and/or mineral supplementation on glomerular and tubular dysfunction in type 2 diabetes. Diabetes Care 28, 2458–2464 (2005).

    Article  PubMed  Google Scholar 

  98. Goicoechea, M. et al. Effect of allopurinol in chronic kidney disease progression and cardiovascular risk. Clin. J. Am. Soc. Nephrol. 5, 1388–1393 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Yokoyama, M. & Hirata, K. Endothelial nitric oxide synthase uncoupling: Is it a physiological mechanism of endothelium-dependent relaxation in cerebral artery? Cardiovasc. Res. 73, 8–9 (2007).

    Article  CAS  PubMed  Google Scholar 

  100. Versari, D., Daghini, E., Virdis, A., Chiadoni, L. & Taddei, S. Endothelium-dependent contractions and endothelial dysfunction in human hypertension. Br. J. Pharmacol. 157, 527–536 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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  1. Renal Unit, Lister Hospital, Coreys Mill Lane, SG1 4AB, Stevenage, UK

    Dhruv K. Singh & Ken Farrington

  2. Department of Diabetes and Endocrinology, Queen Elizabeth II Hospital, AL7 4HQ, Welwyn Garden City, UK

    Peter Winocour

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D. K. Singh researched the data for the article. All authors provided a substantial contribution to discussions of the content, contributed equally to writing the article and reviewed and/or edited the manuscript before submission.

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Singh, D., Winocour, P. & Farrington, K. Oxidative stress in early diabetic nephropathy: fueling the fire. Nat Rev Endocrinol 7, 176–184 (2011). https://doi.org/10.1038/nrendo.2010.212

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