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Cellular mechanisms and treatment of diabetes vascular complications converge on reactive oxygen species

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Abstract

High glucose activates a myriad of signaling and gene expression pathways in non-insulin-dependent target cells causing diabetes complications. One of the earliest responses to high glucose by vascular cells is the generation of reactive oxygen species (ROS) that act directly on intracellular proteins and DNA, or indirectly as second messengers, transforming these cells into disease phenotypes. ROS are produced by mitochondria and/or NADPH oxidase in all target cells exposed to high glucose studied to date. Reports using cell cultures and diabetic animal models indicate that inhibition of ROS generation prevents the amplification of signaling and gene expression that are implicated in vascular complications. These models convincingly demonstrate that maneuvers preventing ROS production attenuate or completely abrogate early micro- and macrovascular end-organ damage of diabetes, including nephropathy, retinopathy, and large-vessel atherosclerosis. Attention now turns to the development of more effective antioxidants that could be used in clinical trials in the prevention and treatment of diabetes complications. References and Recommended Reading

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References and Recommended Reading

  1. Sowers JR, Stump CS: Insights into the biology of diabetes vascular disease: What’s new? Am J Hypertens 2004, 17:S2-S6.

    Article  CAS  Google Scholar 

  2. Giorgino F, Laviola L, Cavallo Perin P, et al.: Factors associated with progression to macroalbuminuria in microalbuminuric type 1 diabetes patients: the EURODIAB Prospective Complications Study. Diabetologia 2004, 47:1020–1028.

    Article  PubMed  CAS  Google Scholar 

  3. Bowden DW: Genetics of diabetes complications. Curr Diab Rep 2002, 2:191–200.

    PubMed  Google Scholar 

  4. Obrosova IG, Minchenko AG, Vasupuram R, et al.: Aldose reductase inhibitor fidarestat prevents retinal oxidative stress and vascular endothelial growth factor overexpression in streptozotocin-diabetic rats. Diabetes 2003, 52:864–871.

    Article  PubMed  CAS  Google Scholar 

  5. Williams B, Gallacher B, Patel H, Orme C: Glucose-induced protein kinase C activation regulates vascular permeability factor mRNA expression and peptide production by human vascular smooth muscle cells in vitro. Diabetes 1997, 46:1497–1503.

    Article  PubMed  CAS  Google Scholar 

  6. Kim NH, Jung HH, Cha DR, Choi DS: Expression of vascular endothelial growth factor in response to high glucose in rat mesangial cells. J Endocrinol 2000, 165:617–624.

    Article  PubMed  CAS  Google Scholar 

  7. Ziyadeh FN, Sharma K, Eriksen M, Wolf G: Stimulation of collagen gene expression and protein synthesis in murine mesangial cells by high glucose is mediated by autocrine activation of transforming growth factor-beta. J Clin Invest 1994, 93:536–542.

    PubMed  CAS  Google Scholar 

  8. Hargrove G, Dufresne J, Whiteside C, et al.: Diabetes mellitus increases endothelin-1 gene transcription in rat kidney. Kidney Int 2000, 58:1534–1545.

    Article  PubMed  CAS  Google Scholar 

  9. Haneda M, Koya D, Isono M, Kikkawa R: Overview of glucose signaling in mesangial cells in diabetic nephropathy. J Am Soc Nephrol 2003, 14:1374–1382. A review of the mesangial cell signaling mechanisms activated in high glucose contributing to early progressive nephropathy.

    Article  PubMed  Google Scholar 

  10. Aiello LP, Bursell SE, Clermont A, et al.: Vascular endothelial growth factor-induced retinal permeability is mediated by protein kinase C in vivo and suppressed by an orally effective betaisoform-selective inhibitor. Diabetes 1997, 46:1473–1480.

    Article  PubMed  CAS  Google Scholar 

  11. Ishii H, Koya D, King GL: Protein kinase C activation and its role in the development of vascular complications in diabetes mellitus. J Mol Med 1998, 76:21–31.

    Article  PubMed  CAS  Google Scholar 

  12. Lee GT, Ha H, Jung M, et al.: Delayed treatment with lithospermate B attenuates experimental diabetic renal injury. J Am Soc Nephrol 2003, 14:709–720.

    Article  PubMed  CAS  Google Scholar 

  13. Glogowski EA, Tsiani E, Zhou X, et al.: High glucose alters the response of mesangial cell protein kinase C isoforms to endothelin-1. Kidney Int 1999, 55:486–499.

    Article  PubMed  CAS  Google Scholar 

  14. Tsiani E, Lekas P, Fantus IG, Whiteside CI: Activation of glomerular mesangial cell p38 MAPK by endothelin-1, angiotensin II and platelet-derived growth factor is enhanced in high glucose. Am J Physiol (Endocrinology) 2002, 282:E161-E169.

    CAS  Google Scholar 

  15. Whiteside CI, Dlugosz JA: Mesangial cell protein kinase C isozyme activation in the diabetic milieu. Am J Physiol Renal Physiol 2002, 282:F975-F980. A review of the mechanisms causing protein kinase C activation by high glucose and growth factors that alter mesangial cell function in high glucose.

    PubMed  CAS  Google Scholar 

  16. Dlugosz JA, Munk S, Kapor-Drezgic J, et al.: Stretch-induced mesangial cell ERK1/ERK2 activation is enhanced in high glucose by decreased dephosphorylation. Am J Physiol Renal Physiol 2000, 279:F688-F697.

    PubMed  CAS  Google Scholar 

  17. Ishii H, Jirousek MR, Koya D, et al.: Amelioration of vascular dysfunctions in diabetic rats by an oral PKC beta inhibitor. Science 1996, 272:728–731. Original report identifying the central role of protein kinase C-beta in the pathogenesis of early microvascular complications of diabetes, including retinopathy and nephropathy.

    Article  PubMed  CAS  Google Scholar 

  18. Koya D, King GL: Protein kinase C activation and the development of diabetic complications. Diabetes 1998, 47:859–866.

    Article  PubMed  CAS  Google Scholar 

  19. Koya D, Jirousek MR, Lin YW, et al.: Characterization of protein kinase C beta isoform activation on the gene expression of transforming growth factor-beta, extracellular matrix components and prostenoids in the glomeruli of diabetic rats. J Clin Invest 1997, 100:115–126.

    Article  PubMed  CAS  Google Scholar 

  20. Koya DJ, Haneda M, Nakagawa H, et al.: Amelioration of accelerated diabetic mesangial expansion by treatment with a PKC beta inhibitor in diabetic db/db mice, a rodent model for type 2 diabetes. FASEB J 2000, 14:439–447.

    PubMed  CAS  Google Scholar 

  21. Touyz RM, Schiffrin EL: Reactive oxygen species in vascular biology: implications in hypertension. Histochem Cell Biol 2004, 122:339–352.

    Article  PubMed  CAS  Google Scholar 

  22. Wassman S, Wassman K, Nichenig G: Modulation of oxidant and antioxidant enzyme expression and function in vascular cells. Hypertension 2004, 44:381–386.

    Article  CAS  Google Scholar 

  23. Taniyama Y, Griendling KK: Reactive oxygen species in the vasculature: molecular and cellular mechanisms. Hypertension 2003, 42:1075–1081. A comprehensive review of the role of reactive oxygen species in normal and dysfunctional states contributing to vascular disease.

    Article  PubMed  CAS  Google Scholar 

  24. Giugliano D, Ceriello A, Paolisso G: Oxidative stress and diabetic vascular complications. Diabetes Care 1996, 19:257–267.

    Article  PubMed  CAS  Google Scholar 

  25. Touyz RM: Reactive oxygen species and angiotensin II signaling in vascular cells - implications in cardiovascular disease. Braz J Med Biol Res 2004, 37:1263–1273.

    Article  PubMed  CAS  Google Scholar 

  26. Brownlee M: Biochemistry and molecular cell biology of diabetic complications. Nature 2001, 414:813–820. An in-depth review of the generation of mitochondrial reactive oxygen species leading to inhibition of GAPDH, consequent activation of pathways fed by glycolytic intermediates, and pathogenesis of diabetes complications.

    Article  PubMed  CAS  Google Scholar 

  27. Du XL, Edelstein D, Rossetti L, et al.: Hyperglycemia-induced mitochondrial superoxide overproduction activates the hexosamine pathway and induces plasminogenn activator inhibitor-1 expression by increasing Sp-1 glycosylation. Proc Natl Acad Sci U S A 2000, 97:12222–12226.

    Article  PubMed  CAS  Google Scholar 

  28. Nishikawa T, Edelstein D, Du XL, et al.: Normalizing mitochondrial superoxide production blocks three pathways of hyperglycemic damage. Nature 2000, 404:787–790. A landmark study identifying the relationship between the generation of mitochondrial reactive oxygen species and the stimulation of metabolic and signaling pathways leading to diabetes complications.

    Article  PubMed  CAS  Google Scholar 

  29. Du X, Matsumura T, Edelstein D, et al.: Inhibition of GAPDH activity by poly(ADP-ribose) polymerase activates three major pathways of hyperglycemic damage in endothelial cells. J Clin Invest 2003, 112:1049–1057.

    Article  PubMed  CAS  Google Scholar 

  30. Van Heerebeek L, Meischl C, Stooker W, et al.: NADPH oxidase(s): new source(s) or reactive oxygen species in the vascular system? J Clin Pathol 2002, 55:561–568.

    Article  PubMed  Google Scholar 

  31. Li JM, Shah AM: Endothelial cell superoxide generation: regulation and relevance for cardiovascular pathophysiology. Am J Physiol Regul Integr Comp Physiol 2004, 287:R1014–1030.

    PubMed  CAS  Google Scholar 

  32. Lasségue B, Clempus RE: Vascular NAD(P)H oxidases: specific features, expression and regulation. Am J Physiol Regul Integr Comp Physiol 2003, 285:R277–297. A detailed review describing all aspects of the structure and function of NADPH oxidase as it relates to vascular cells in normal and disease states.

    PubMed  Google Scholar 

  33. Griendling KK, FitzGerald GA: Oxidative stress and cardiovascular injury Part I: Basic mechanisms and in vivo monitoring of ROS. Circulation 2003, 108:1912–1916.

    Article  PubMed  Google Scholar 

  34. Inoguchi T, Li P, Umeda F, et al.: High glucose level and free fatty acid stimulate reactive oxygen species production through protein kinase C-dependent activation of NADPH oxidase in cultured vascular cells. Diabetes 2000, 49:1939–1945.

    Article  PubMed  CAS  Google Scholar 

  35. Christ M, Bauersachs J, Liebetrau C, et al.: Glucose increases endothelial-dependent superoxide formation in coronary arteries by NADPH oxidase activation: attenuation by 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitor atorvastatin. Diabetes 2002, 51:2648–2652.

    Article  PubMed  CAS  Google Scholar 

  36. Inoguchi T, Sonta T, Tsubouchi H, et al.: Protein kinase Cdependent increase in reactive oxygen species (ROS) production in vascular tissues of diabetes: role of vascular NADPH oxidase. J Am Soc Nephrol 2003, 14:S227-S332.

    Article  PubMed  CAS  Google Scholar 

  37. Hua H, Munk S, Goldberg H, et al.: High glucose-suppressed endothelin-1 Ca2+ signaling via NADPH oxidase and diacylglycerol-sensitive protein kinase C isozymes in mesangial cells. J Biol Chem 2003, 278:33951–33962.

    Article  PubMed  CAS  Google Scholar 

  38. Fontayne A, Dang PM, Gougerot-Pocidalo MA, El-Benna J:Phosphorylation of p47phox sites by PKC alpha, beta II, delta and zeta: effect on binding to p22phox and on NADPH oxidase activation. Biochemistry 2002, 41:7743–7750.

    Article  PubMed  CAS  Google Scholar 

  39. Harrison DG, Cai H, Landmesser U, Griendling KK: Interactions of angiotensin II with NAD(P)H oxidase, oxidant stress and cardiovascular disease. J Renin Angiotensin Aldosterone Syst 2003, 4:51–61.

    PubMed  CAS  Google Scholar 

  40. Colavitti R, Pani G, Bedogni R, et al.: Reactive oxygen species as downstream mediators of angiogenic signaling by vascular endothelial growth factor receptor-2/KDR. J Biol Chem 2002, 277:3101–3108.

    Article  PubMed  CAS  Google Scholar 

  41. Gorin Y, Ricono JM, Kim NH, et al.: Nox4 mediates angiotensin II-induced activation of Akt/protein kinase B in mesangial cells. Am J Physiol Renal Physiol 2003, 285:F219-F229.

    PubMed  CAS  Google Scholar 

  42. Kelly DJ, Zhang Y, Hepper C, et al.: Protein kinase C beta inhibition attenuates the progression of experimental diabetic nephropathy in the presence of continued hypertension. Diabetes 2003, 52:512–518.

    Article  PubMed  CAS  Google Scholar 

  43. Wautier MP, Chappey O, Corda S, et al.: Activation of NADPH oxidase by AGE links oxidative stress to altered gene expression via RAGE. Am J Physiol Endocrinol Metab 2001, 280:E685-E694.

    PubMed  CAS  Google Scholar 

  44. Wautier JL, Schmidt AM: Protein glycation: a firm link to endothelial cell dysfunction. Circ Res 2004, 95:233–238.

    Article  PubMed  CAS  Google Scholar 

  45. Bucciarelli LG, Wendt T, Qu W, et al.: RAGE blockade stabilizes established atherosclerosis in diabetes apolipoprotein E-null mice. Circulation 2002, 106:2827–2835.

    Article  PubMed  CAS  Google Scholar 

  46. Hammes H-P, Du X, Edelstein D, et al.: Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy. Nature Medicine 2003, 9:294–299.

    Article  PubMed  CAS  Google Scholar 

  47. Friedman J, Peleg E, Kagan T, et al.: Oxidative stress in hypertensive, diabetic and diabetic hypertensive rats. Am J Hypertens 2003, 16:1049–1052.

    Article  PubMed  CAS  Google Scholar 

  48. Koya D, Hayashi K, Kitada M, et al.: Effects of antioxidants in diabetes-induced oxidative stress in the glomeruli of diabetic rats. J Am Soc Nephrol 2003, 14:S250-S253.

    Article  PubMed  CAS  Google Scholar 

  49. Melhem MF, Craven PA, DeRubertis FR: Effects of dietary supplementation of alpha-lipoic acid on early glomerular injury in diabetes mellitus. J Am Soc Nephrol 2001, 12:124–133.

    PubMed  CAS  Google Scholar 

  50. Melhem MF, Craven PA, Liachenko J, DeRubertis FR: Alphalipoic acid attenuates hyperglycemia and prevents glomerular mesangial matrix expansion in diabetes. J Am Soc Nephrol 2002, 13:108–116.

    PubMed  CAS  Google Scholar 

  51. Ha H, Yu MR, Choi YJ, Lee HB: Activation of protein kinase Cdelta and C-epsilon by oxidative stress in early diabetic rat kidney. Am J Kidney Dis 2001, 38:S204-S207.

    PubMed  CAS  Google Scholar 

  52. Craven PA, Melhem MF, Phillips SL, DeRubetis FR: Overexpression of Cu2+/Zn2+ superoxide dismutase protects against early diabetic glomerular injury in transgenic mice. Diabetes 2001, 50:2114–2125.

    Article  PubMed  CAS  Google Scholar 

  53. DeRubertis FR, Craven PA, Melhem MF, Salah EM: Attenuation of renal injury in db/db mice overexpressing superoxide dismutase: evidence for reduced superoxide-nitric oxide interaction. Diabetes 2004, 53:762–768. This study provides convincing evidence that superoxide anion generation in a model of type 2 diabetes is necessary for renal disease due to hyperglycemia.

    Article  PubMed  CAS  Google Scholar 

  54. Channon KM, Grazik TJ: Mechanisms of superoxide production in human blood vessels: relationship to endothelial dysfunction, clinical and genetic risk factors. J Physiol Pharmacol 2002, 53:515–524.

    PubMed  CAS  Google Scholar 

  55. Guzik TJ, Mussa S, Gastaldi D, et al.: Mechanisms of increased vascular superoxide production in human diabetes mellitus: role of NADPH oxidase and enthothelial nitric oxide synthase. Circulation 2002, 105:1656–1662.

    Article  PubMed  CAS  Google Scholar 

  56. Miller FJJr, Gutterman DD, Rios CD, et al.: Superoxide production in vascular smooth muscle contributes to oxidative stress and impaired relaxation in atherosclerosis. Circ Res 1998, 82:1298–1305.

    PubMed  CAS  Google Scholar 

  57. Sz∁s K, Lasségue B, Sorescu D, et al.: Upregulation of Noxbased NADPH oxidases in restenosis after carotid injury. Arterioscler Thromb Vasc Biol 2002, 22:21–27.

    Article  Google Scholar 

  58. Patterson C, Ruef J, Madamanchi NR, et al.: Stimulation of a vascular smooth muscle cell NADPH oxidase by thrombin: evidence that p47phox may participate in forming this oxidase in vitro and in vivo. J Biol Chem 1999, 274:19814–19822.

    Article  PubMed  CAS  Google Scholar 

  59. Kalinina N, Agrotis A, Tararak E, et al.: Cytochrome b558-dependent NADPH oxidase-phox units in smooth muscle and macrophages of atherosclerotic lesions. Arterioscler Thromb Vasc Biol 2002, 22:2037–20443.

    Article  PubMed  CAS  Google Scholar 

  60. Barry-Lane PA, Patterson C, van der Merwe M, et al.: p47phox is required for atherosclerotic lesion progression in ApoE-/-mice. J Clin Invest 2001, 108:1513–1522.

    Article  PubMed  CAS  Google Scholar 

  61. Lasségue B, Griendling KK: Reactive oxygen species in hypertension. Am J Hypertens 2004, 17:852–860.

    Article  PubMed  CAS  Google Scholar 

  62. Inoue I, Goto S, Matsunaga T, et al.: The ligands/activators for peroxisome proliferator-activated receptor alpha (PPARalpha) and PPARgamma increase Cu2+,Zn2+ -superoxide dismutase and decrease p22phox message expressions in primary endothelial cells. Metabolism 2001, 50:3–11.

    Article  PubMed  CAS  Google Scholar 

  63. Inoue I, Goto S, Mizotani K, et al.: Lipophilic HMG-CoA reductase inhibitor has an anti-inflammatory effect: reduction of mRNA levels for interleukin-1beta, interleukin-6, cyclooxygenase-2, and p22phox by regulation of peroxisome proliferators-activated receptor alpha (PPARalpha) in primary endothelial cells. Life Sci 2000, 67:863–876.

    Article  PubMed  CAS  Google Scholar 

  64. Wassmann S, Laufs U, Muller K, et al.: Cellular antioxidant effects of atorvastatin in vitro and in vivo. Arterioscler Thromb Vasc Biol 2002, 22:300–305.

    Article  PubMed  CAS  Google Scholar 

  65. Seshiah PN, Weber DS, Rocic P, et al.: Angiotensin II stimulation of NADPH oxidase activity: upstream mediators. Circ Res 2002, 91:406–413.

    Article  PubMed  CAS  Google Scholar 

  66. Kong G, Lee S, Kim KS: Inhibition of rac1 reduces PDGFinduced reactive oxygen species and proliferation in vascular smooth muscle cells. J Korean Med Sci 2001, 16:712–718.

    PubMed  CAS  Google Scholar 

  67. Cifuentes ME, Rey FE, Carretero OA, Pagano PJ: Upregulation of p67phox and gp91phox in aortas from angiotensin-infused mice. Am J Physiol Heart Circ Physiol 2000, 279:H2234-H2240.

    PubMed  CAS  Google Scholar 

  68. Didion SP, Ryan MJ, Baumbach GL, et al.: Superoxide contributes to vascular dysfunction in mice that express human renin and angiotensinogen. Am J Physiol Heart Circ Physiol 2002, 283:H1569-H1576.

    PubMed  CAS  Google Scholar 

  69. Shastri S, Gopalakrishnan V, Poduri R, Di Wang H: Tempol selectively attenuates angiotensin II evoked vasoconstrictor responses in spontaneously hypertensive rats. J Hypertens 2002, 20:1381–1391.

    Article  PubMed  CAS  Google Scholar 

  70. Nishiyama A, Fukui T, Fujisawa Y, et al.: Systemic and regional hemodynamic responses to tempol in angiotensin II-infused hypertensive rats. Hypertension 2001, 37:77–83.

    PubMed  CAS  Google Scholar 

  71. Ortiz MC, Manriquez MC, Romero JC, Juncos LA: Antioxidants block angiotensin II-induced increases in blood pressure and endothelin. Hypertension 1998, 32:331–337.

    Google Scholar 

  72. Wang HD, Johns DG, Xu S, Cohen RA: Role of superoxide anion in regulating pressor and vascular hypertrophic response to angiotensin II. Am J Physiol Heart Circ Physiol 2002, 282:H1697-H1702.

    PubMed  CAS  Google Scholar 

  73. Dobrian AD, Schriver SD, Prewitt RL: Role of angiotensin II and free radicals in blood pressure regulation in a rat model of renal hypertension. Hypertension 2001, 38:361–366.

    PubMed  CAS  Google Scholar 

  74. Zalba G, San Jose G, Moreno MU, et al.: Oxidative stress in arterial hypertension: role of NADPH oxidase. Hypertension 2001, 38:1395–1399.

    PubMed  CAS  Google Scholar 

  75. Delles C, Schneider MP, Oehmer S, et al.: Increased response of renal perfusion to the antioxidant vitamin C in type 2 diabetes. Nephrol Dial Transplant 2004, 19:2513–2518.

    Article  PubMed  CAS  Google Scholar 

  76. Lonn E, Yusuf S, Hoogwerf B, et al., on behalf of theHeart Outcomes Prevention Evaluation Investigators: Effects of vitamin E on cardiovascular and microvascular outcomes in high-risk patients with diabetes. Diabetes Care 2002, 25:1919–1927.

    Article  PubMed  CAS  Google Scholar 

  77. Green K, Brand MD, Murphy MP: Prevention of mitochondrial oxidative damage as a therapeutic strategy in diabetes. Diabetes 2004, 53:S110-S118.

    Article  PubMed  CAS  Google Scholar 

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  1. Department of Medicine, University of Toronto, 1 King’s College Circle, Room 2113, M5S 1A8, Toronto, ON, Canada

    Catharine I. Whiteside MD, PhD

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Whiteside, C.I. Cellular mechanisms and treatment of diabetes vascular complications converge on reactive oxygen species. Current Science Inc 7, 148–154 (2005). https://doi.org/10.1007/s11906-005-0090-4

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