Table of Contents Author Guidelines Submit a Manuscript
Experimental Diabetes Research
Volume 2007 (2007), Article ID 43603, 12 pages
http://dx.doi.org/10.1155/2007/43603
Review Article

Oxidative Stress and Diabetic Retinopathy

Kresge Eye Institute, Wayne State University, Detroit 48201, MI, USA

Received 21 December 2006; Accepted 8 February 2007

Academic Editor: Subrata Chakrabarti

Copyright © 2007 Renu A. Kowluru and Pooi-See Chan. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. S. Sharma, A. Oliver-Fernandez, W. Liu, P. Buchholz, and J. Walt, “The impact of diabetic retinopathy on health-related quality of life,” Current Opinion in Ophthalmology, vol. 16, no. 3, pp. 155–159, 2005. View at Publisher · View at Google Scholar
  2. R. N. Frank, “Diabetic retinopathy,” New England Journal of Medicine, vol. 350, no. 1, pp. 48–58, 2004. View at Publisher · View at Google Scholar · View at PubMed
  3. G. W. Aylward, “Progressive changes in diabetics and their management,” Eye, vol. 19, no. 10, pp. 1115–1118, 2005. View at Publisher · View at Google Scholar · View at PubMed
  4. W. G. Robison Jr., P. F. Kador, and J. H. Kinoshita, “Early retinal microangiopathy: prevention with aldose reductase inhibitors,” Diabetic Medicine, vol. 2, no. 3, pp. 196–199, 1985.
  5. N. S. Harhaj and D. A. Antonetti, “Regulation of tight junctions and loss of barrier function in pathophysiology,” International Journal of Biochemistry and Cell Biology, vol. 36, no. 7, pp. 1206–1237, 2004. View at Publisher · View at Google Scholar · View at PubMed
  6. L. P. Aiello, T. W. Gardner, and G. L. King et al., “Diabetic retinopathy,” Diabetes Care, vol. 21, no. 1, pp. 143–156, 1998.
  7. R. N. Frank, “On the pathogenesis of diabetic retinopathy: a 1990 update,” Ophthalmology, vol. 98, no. 5, pp. 586–593, 1991.
  8. R. L. Engerman, M. D. Davis, and J. M. B. Bloodworth Jr., “Retinopathy in experimental diabetes: its relevance to diabetic retinopathy in man,” in Diabetes, Proceedings of the 7th Congress of the International Diabetes Federation, R. Rodriguez and J. Vallance-Owen, Eds., pp. 261–267, Excerpta Medica, Amsterdam, The Netherlands, 1971.
  9. T. S. Kern, R. A. Kowluru, and R. L. Engerman, Questions Raised by Studies of Experimental Diabetic Retinopathy, Elsevier Science B. V., Osaka, Japan, 1994.
  10. M. Mizutani, T. S. Kern, and M. Lorenzi, “Accelerated death of retinal microvascular cells in human and experimental diabetic retinopathy,” Journal of Clinical Investigation, vol. 97, no. 12, pp. 2883–2890, 1996.
  11. T. S. Kern, J. Tang, and M. Mizutani et al., “Response of capillary cell death to aminoguanidine predicts the development of retinopathy: comparison of diabetes and galactosemia,” Investigative Ophthalmology & Visual Science, vol. 41, no. 12, pp. 3972–3978, 2000.
  12. R. A. Kowluru and S. Odenbach, “Effect of long-term administration of α-lipoic acid on retinal capillary cell death and the development of retinopathy in diabetic rats,” Diabetes, vol. 53, no. 12, pp. 3233–3238, 2004.
  13. A. M. Joussen, V. Poulaki, and M. L. Le et al., “A central role for inflammation in the pathogenesis of diabetic retinopathy,” FASEB Journal, vol. 18, no. 12, pp. 1450–1452, 2004. View at Publisher · View at Google Scholar · View at PubMed
  14. P. Xia, T. Inoguchi, T. S. Kern, R. L. Engerman, P. J. Oates, and G. L. King, “Characterization of the mechanism for the chronic activation of diacylglycerol-protein kinase C pathway in diabetes and hypergalactosemia,” Diabetes, vol. 43, no. 9, pp. 1122–1129, 1994.
  15. R. A. Kowluru, M. R. Jirousek, L. Stramm, N. Farid, R. L. Engerman, and T. S. Kern, “Abnormalities of retinal metabolism in diabetes or experimental galactosemia. V. Relationship between protein kinase C and APTases,” Diabetes, vol. 47, no. 3, pp. 464–469, 1998.
  16. R. A. Kowluru, J. Tang, and T. S. Kern, “Abnormalities of retinal metabolism in diabetes and experimental galactosemia. VII. Effect of long-term administration of antioxidants on the development of retinopathy,” Diabetes, vol. 50, no. 8, pp. 1938–1942, 2001.
  17. R. A. Kowluru, “Diabetes-induced elevations in retinal oxidative stress, protein kinase C and nitric oxide are interrelated,” Acta Diabetologica, vol. 38, no. 4, pp. 179–185, 2001. View at Publisher · View at Google Scholar
  18. R. A. Kowluru, A. Kowluru, S. Chakrabarti, and Z. Khan, “Potential contributory role of H-Ras, a small G-protein, in the development of retinopathy in diabetic rats,” Diabetes, vol. 53, no. 3, pp. 775–783, 2004.
  19. R. A. Kowluru, P. Koppolu, S. Chakrabarti, and S. Chen, “Diabetes-induced activation of nuclear transcriptional factor in the retina, and its inhibition by antioxidants,” Free Radical Research, vol. 37, no. 11, pp. 1169–1180, 2003. View at Publisher · View at Google Scholar
  20. R. A. Kowluru and P. Koppolu, “Diabetes-induced activation of caspase-3 in retina: effect of antioxidant therapy,” Free Radical Research, vol. 36, no. 9, pp. 993–999, 2002. View at Publisher · View at Google Scholar
  21. A. R. Bhavsar, “Diabetic retinopathy: the latest in current management,” Retina, vol. 26, no. 6 supplement, pp. S71–S79, 2006. View at Publisher · View at Google Scholar
  22. Diabetes Control and Complications Trial Research Group, “Hypoglycemia in the diabetes control and complications trial,” Diabetes, vol. 46, no. 2, pp. 271–286, 1997.
  23. W. Dröge, “Free radicals in the physiological control of cell function,” Physiological Reviews, vol. 82, no. 1, pp. 47–95, 2002.
  24. R. G. Cutler, “Oxidative stress profiling—part I. Its potential importance in the optimization of human health,” Annals of the New York Academy of Sciences, vol. 1055, pp. 93–135, 2005. View at Publisher · View at Google Scholar · View at PubMed
  25. J. W. Baynes, “Role of oxidative stress in development of complications in diabetes,” Diabetes, vol. 40, no. 4, pp. 405–412, 1991.
  26. E. L. Feldman, “Oxidative stress and diabetic neuropathy: a new understanding of an old problem,” Journal of Clinical Investigation, vol. 111, no. 4, pp. 431–433, 2003. View at Publisher · View at Google Scholar
  27. H. Ha and K. H. Kim, “Pathogenesis of diabetic nephropathy: the role of oxidative stress and protein kinase C,” Diabetes Research and Clinical Practice, vol. 45, no. 2-3, pp. 147–151, 1999. View at Publisher · View at Google Scholar
  28. Y. Hinokio, S. Suzuki, M. Hirai, C. Suzuki, M. Suzuki, and T. Toyota, “Urinary excretion of 8-oxo-7, 8-dihydro-2-deoxyguanosine as a predictor of the development of diabetic nephropathy,” Diabetologia, vol. 45, no. 6, pp. 877–882, 2002. View at Publisher · View at Google Scholar · View at PubMed
  29. L. Cai and Y. J. Kang, “Oxidative stress and diabetic cardiomyopathy: a brief review,” Cardiovascular Toxicology, vol. 1, no. 3, pp. 181–193, 2001. View at Publisher · View at Google Scholar
  30. R. A. Kowluru, “Effect of reinstitution of good glycemic control on retinal oxidative stress and nitrative stress in diabetic rats,” Diabetes, vol. 52, no. 3, pp. 818–823, 2003.
  31. S. A. Wohaieb and D. V. Godin, “Alterations in free radical tissue-defense mechanisms in streptozocin-induced diabetes in rat. Effects of insulin treatment,” Diabetes, vol. 36, no. 9, pp. 1014–1018, 1987.
  32. J. W. Baynes and S. R. Thorpe, “Role of oxidative stress in diabetic complications: a new perspective on an old paradigm,” Diabetes, vol. 48, no. 1, pp. 1–9, 1999.
  33. K. Haskins, B. Bradley, and K. Powers et al., “Oxidative stress in type 1 diabetes,” Annals of the New York Academy of Sciences, vol. 1005, pp. 43–54, 2003. View at Publisher · View at Google Scholar
  34. M. Brownlee, “Biochemistry and molecular cell biology of diabetic complications,” Nature, vol. 414, no. 6865, pp. 813–820, 2001. View at Publisher · View at Google Scholar · View at PubMed
  35. R. E. Anderson, L. M. Rapp, and R. D. Wiegand, “Lipid peroxidation and retinal degeneration,” Current Eye Research, vol. 3, no. 1, pp. 223–227, 1984.
  36. R. A. Kowluru and S. N. Abbas, “Diabetes-induced mitochondrial dysfunction in the retina,” Investigative Ophthalmology & Visual Science, vol. 44, no. 12, pp. 5327–5334, 2003. View at Publisher · View at Google Scholar
  37. Y. Du, C. M. Miller, and T. S. Kern, “Hyperglycemia increases mitochondrial superoxide in retina and retinal cells,” Free Radical Biology and Medicine, vol. 35, no. 11, pp. 1491–1499, 2003. View at Publisher · View at Google Scholar
  38. Y. Cui, X. Xu, and H. Bi et al., “Expression modification of uncoupling proteins and MnSOD in retinal endothelial cells and pericytes induced by high glucose: the role of reactive oxygen species in diabetic retinopathy,” Experimental Eye Research, vol. 83, no. 4, pp. 807–816, 2006. View at Publisher · View at Google Scholar · View at PubMed
  39. E. A. Ellis, D. L. Guberski, M. Somogyi-Mann, and M. B. Grant, “Increased H2O2, vascular endothelial growth factor and receptors in the retina of the BBZ/WOR diabetic rat,” Free Radical Biology and Medicine, vol. 28, no. 1, pp. 91–101, 2000. View at Publisher · View at Google Scholar
  40. R. A. Kowluru and P. Koppolu, “Termination of experimental galactosemia in rats, and progression of retinal metabolic abnormalities,” Investigative Ophthalmology & Visual Science, vol. 43, no. 10, pp. 3287–3291, 2002.
  41. A. Meister, “Glutathione metabolism and its selective modification,” Journal of Biological Chemistry, vol. 263, no. 33, pp. 17205–17208, 1988.
  42. T. S. Kern, R. A. Kowluru, and R. L. Engerman, “Abnormalities of retinal metabolism in diabetes or galactosemia: ATPases and glutathione,” Investigative Ophthalmology & Visual Science, vol. 35, no. 7, pp. 2962–2967, 1994.
  43. R. A. Kowluru, T. S. Kern, and R. L. Engerman, “Abnormalities of retinal metabolism in diabetes or galactosemia II. Comparison of γ-glutamyl transpeptidase in retina and cerebral cortex, and effects of antioxidant therapy,” Current Eye Research, vol. 13, no. 12, pp. 891–896, 1994.
  44. R. A. Kowluru, T. S. Kern, and R. L. Engerman, “Abnormalities of retinal metabolism in diabetes or experimental galactosemia. IV. Antioxidant defense system,” Free Radical Biology and Medicine, vol. 22, no. 4, pp. 587–592, 1996. View at Publisher · View at Google Scholar
  45. E. S. Ford, A. H. Mokdad, W. H. Giles, and D. W. Brown, “The metabolic syndrome and antioxidant concentrations: findings from the Third National Health and Nutrition Examination Survey,” Diabetes, vol. 52, no. 9, pp. 2346–2352, 2003.
  46. R. L. Engerman, T. S. Kern, and M. E. Larson, “Nerve conduction and aldose reductase inhibition during 5 years of diabetes or galactosaemia in dogs,” Diabetologia, vol. 37, no. 2, pp. 141–144, 1994. View at Publisher · View at Google Scholar
  47. P. J. Beisswenger, S. K. Howell, K. Smith, and B. S. Szwergold, “Glyceraldehyde-3-phosphate dehydrogenase activity as an independent modifier of methylglyoxal levels in diabetes,” Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, vol. 1637, no. 1, pp. 98–106, 2003. View at Publisher · View at Google Scholar
  48. B. Stauble, D. Boscoboinik, A. Tasinato, and A. Azzi, “Modulation of activator protein-1 (AP-1) transcription factor and protein kinase C by hydrogen peroxide and D-α-tocopherol in vascular smooth muscle cells,” European Journal of Biochemistry, vol. 226, no. 2, pp. 393–402, 1994. View at Publisher · View at Google Scholar
  49. D. Koya and G. L. King, “Protein kinase C activation and the development of diabetic complications,” Diabetes, vol. 47, no. 6, pp. 859–866, 1998.
  50. X.-L. Du, D. Edelstein, and L. Rossetti et al., “Hyperglycemia-induced mitochondrial superoxide overproduction activates the hexosamine pathway and induces plasminogen activator inhibitor-1 expression by increasing Sp1 glycosylation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 22, pp. 12222–12226, 2000. View at Publisher · View at Google Scholar · View at PubMed
  51. R. B. Caldwell, M. Bartoli, and M. A. Behzadian et al., “Vascular endothelial growth factor and diabetic retinopathy: role of oxidative stress,” Current Drug Targets, vol. 6, no. 4, pp. 511–524, 2005. View at Publisher · View at Google Scholar
  52. B. J. DeBosch, E. Baur, B. K. Deo, M. Hiraoka, and A. K. Kumagai, “Effects of insulin-like growth factor-1 on retinal endothelial cell glucose transport and proliferation,” Journal of Neurochemistry, vol. 77, no. 4, pp. 1157–1167, 2001. View at Publisher · View at Google Scholar
  53. R. A. Kowluru, “Diabetic retinopathy: mitochondrial dysfunction and retinal capillary cell death,” Antioxidants & Redox Signaling, vol. 7, no. 11-12, pp. 1581–1587, 2005. View at Publisher · View at Google Scholar · View at PubMed
  54. K. Miwa, J. Nakamura, and Y. Hamada et al., “The role of polyol pathway in glucose-induced apoptosis of cultured retinal pericytes,” Diabetes Research and Clinical Practice, vol. 60, no. 1, pp. 1–9, 2003. View at Publisher · View at Google Scholar
  55. M. A. Glomb and V. M. Monnier, “Mechanism of protein modification by glyoxal and glycolaldehyde, reactive intermediates of the Maillard reaction,” Journal of Biological Chemistry, vol. 270, no. 17, pp. 10017–10026, 1995. View at Publisher · View at Google Scholar
  56. A. W. Stitt, “The role of advanced glycation in the pathogenesis of diabetic retinopathy,” Experimental and Molecular Pathology, vol. 75, no. 1, pp. 95–108, 2003. View at Publisher · View at Google Scholar
  57. A. K. Mohamed, A. Bierhaus, S. Schiekofer, H. Tritschler, R. Ziegler, and P. P. Nawroth, “The role of oxidative stress and NF-κB activation in late diabetic complications,” BioFactors, vol. 10, no. 2-3, pp. 157–167, 1999.
  58. R. A. Kowluru, “Effect of advanced glycation end products on accelerated apoptosis of retinal capillary cells under in vitro conditions,” Life Sciences, vol. 76, no. 9, pp. 1051–1060, 2005. View at Publisher · View at Google Scholar · View at PubMed
  59. R. M. Cowell and J. W. Russell, “Nitrosative injury and antioxidant therapy in the management of diabetic neuropathy,” Journal of Investigative Medicine, vol. 52, no. 1, pp. 33–44, 2004.
  60. H. Ishii, M. R. Jirousek, and D. Koya et al., “Amelioration of vascular dysfunctions in diabetic rats by an oral PKC β inhibitor,” Science, vol. 272, no. 5262, pp. 728–731, 1996. View at Publisher · View at Google Scholar
  61. R. A. Kowluru, T. S. Kern, R. L. Engerman, and D. Armstrong, “Abnormalities of retinal metabolism in diabetes or experimental galactosemia. III. Effects of antioxidants,” Diabetes, vol. 45, no. 9, pp. 1233–1237, 1996.
  62. E. J. Palumbo, J. D. Sweatt, S.-J. Chen, and E. Klann, “Oxidation-induced persistent activation of protein kinase C in hippocampal homogenates,” Biochemical and Biophysical Research Communications, vol. 187, no. 3, pp. 1439–1445, 1992. View at Publisher · View at Google Scholar
  63. T. Oikawa, M. Shimamura, and H. Ashino et al., “Inhibition of angiogenesis by staurosporine, a potent protein kinase inhibitor,” Journal of Antibiotics, vol. 45, no. 7, pp. 1155–1160, 1992.
  64. P. Xia, L. P. Aiello, and H. Ishii et al., “Characterization of vascular endothelial growth factor's effect on the activation of protein kinase C, its isoforms, and endothelial cell growth,” Journal of Clinical Investigation, vol. 98, no. 9, pp. 2018–2026, 1996.
  65. D. Koya, M. R. Jirousek, Y.-W. Lin, H. Ishii, K. Kuboki, and G. L. King, “Characterization of protein kinase C β isoform activation on the gene expression of transforming growth factor-β, extracellular matrix components, and prostanoids in the glomeruli of diabetic rats,” Journal of Clinical Investigation, vol. 100, no. 1, pp. 115–126, 1997.
  66. Y. Wu, G. Wu, and X. Qi et al., “Protein kinase C β inhibitor LY333531 attenuates intercellular adhesion molecule-1 and monocyte chemotactic protein-1 expression in the kidney in diabetic rats,” Journal of Pharmacological Sciences, vol. 101, no. 4, pp. 335–343, 2006. View at Publisher · View at Google Scholar
  67. Y. Ohshiro, R. C. Ma, and Y. Yasuda et al., “Reduction of diabetes-induced oxidative stress, fibrotic cytokine expression, and renal dysfunction in protein kinase Cβ-null mice,” Diabetes, vol. 55, no. 11, pp. 3112–3120, 2006. View at Publisher · View at Google Scholar · View at PubMed
  68. X. Du, T. Matsumura, and D. Edelstein et al., “Inhibition of GAPDH activity by poly(ADP-ribose) polymerase activates three major pathways of hyperglycemic damage in endothelial cells,” Journal of Clinical Investigation, vol. 112, no. 7, pp. 1049–1057, 2003. View at Publisher · View at Google Scholar · View at PubMed
  69. M. Brownlee, “The pathobiology of diabetic complications: a unifying mechanism,” Diabetes, vol. 54, no. 6, pp. 1615–1625, 2005.
  70. P. J. Beisswenger, K. S. Drummond, R. G. Nelson, S. K. Howell, B. S. Szwergold, and M. Mauer, “Susceptibility to diabetic nephropathy is related to dicarbonyl and oxidative stress,” Diabetes, vol. 54, no. 11, pp. 3274–3281, 2005.
  71. T. Ishii, O. Sunami, H. Nakajima, H. Nishio, T. Takeuchi, and F. Hata, “Critical role of sulfenic acid formation of thiols in the inactivation of glyceraldehyde-3-phosphate dehydrogenase by nitric oxide,” Biochemical Pharmacology, vol. 58, no. 1, pp. 133–143, 1999. View at Publisher · View at Google Scholar
  72. G. A. Lutty, D. S. McLeod, C. Merges, A. Diggs, and J. Plouét, “Localization of vascular endothelial growth factor in human retina and choroid,” Archives of Ophthalmology, vol. 114, no. 8, pp. 971–977, 1996.
  73. L. P. Aiello and J.-S. Wong, “Role of vascular endothelial growth factor in diabetic vascular complications,” Kidney International, vol. 58, no. 77, pp. S113–S119, 2000. View at Publisher · View at Google Scholar
  74. M. Lu, M. Kuroki, and S. Amano et al., “Advanced glycation end products increase retinal vascular endothelial growth factor expression,” Journal of Clinical Investigation, vol. 101, no. 6, pp. 1219–1224, 1998.
  75. L. P. Aiello, S.-E. Bursell, and A. Clermont et al., “Vascular endothelial growth factor-induced retinal permeability is mediated by protein kinase C in vivo and suppressed by an orally effective β-isoform-selective inhibitor,” Diabetes, vol. 46, no. 9, pp. 1473–1480, 1997.
  76. R. N. Frank, R. Amin, A. Kennedy, and T. C. Hohman, “An aldose reductase inhibitor and aminoguanidine prevent vascular endothelial growth factor expression in rats with long-term galactosemia,” Archives of Ophthalmology, vol. 115, no. 8, pp. 1036–1047, 1997.
  77. K. Yano, J. R. Bauchat, M. B. Liimatta, D. R. Clemmons, and C. Duan, “Down-regulation of protein kinase C inhibits insulin-like growth factor I-induced vascular smooth muscle cell proliferation, migration, and gene expression,” Endocrinology, vol. 140, no. 10, pp. 4622–4632, 1999. View at Publisher · View at Google Scholar
  78. T. Finkel, “Intracellular redox regulation by the family of small GTPases,” Antioxidants & Redox Signaling, vol. 8, no. 9-10, pp. 1857–1863, 2006. View at Publisher · View at Google Scholar · View at PubMed
  79. T. A. Young, C. C. Cunningham, and S. M. Bailey, “Reactive oxygen species production by the mitochondrial respiratory chain in isolated rat hepatocytes and liver mitochondria: studies using myxothiazol,” Archives of Biochemistry and Biophysics, vol. 405, no. 1, pp. 65–72, 2002. View at Publisher · View at Google Scholar
  80. C. M. Bergamini, S. Gambetti, A. Dondi, and C. Cervellati, “Oxygen, reactive oxygen species and tissue damage,” Current Pharmaceutical Design, vol. 10, no. 14, pp. 1611–1626, 2004. View at Publisher · View at Google Scholar
  81. M. Kanwar, P.-S. Chan, T. S. Kern, and R. A. Kowluru, “Oxidative damage in the retinal mitochondria of diabetic mice: possible protection by superoxide dismutase,” submitted to Investigative Ophthalmology & Visual Science.
  82. R. A. Kowluru, L. Atasi, and Y. S. Ho, “Role of mitochondrial superoxide dismutase in the development of diabetic retinopathy,” Investigative Ophthalmology & Visual Science, vol. 47, no. 4, pp. 1594–1599, 2006. View at Publisher · View at Google Scholar · View at PubMed
  83. R. A. Kowluru, V. Kowluru, Y. Xiong, and Y.-S. Ho, “Overexpression of mitochondrial superoxide dismutase in mice protects the retina from diabetes-induced oxidative stress,” Free Radical Biology and Medicine, vol. 41, no. 8, pp. 1191–1196, 2006. View at Publisher · View at Google Scholar · View at PubMed
  84. J. A. Maassen, L. M. 'T Hart, and E. Van Essen et al., “Mitochondrial diabetes: molecular mechanisms and clinical presentation,” Diabetes, vol. 53, supplement 1, pp. S103–S109, 2004.
  85. R. A. Kowluru, S. N. Abbas, and S. Odenbach, “Reversal of hyperglycemia and diabetic nephropathy: effect of reinstitution of good metabolic control on oxidative stress in the kidney of diabetic rats,” Journal of Diabetes and Its Complications, vol. 18, no. 5, pp. 282–288, 2004. View at Publisher · View at Google Scholar · View at PubMed
  86. R. A. Feit-Leichman, R. Kinouchi, and M. Takeda et al., “Vascular damage in a mouse model of diabetic retinopathy: relation to neuronal and glial changes,” Investigative Ophthalmology & Visual Science, vol. 46, no. 11, pp. 4281–4287, 2005. View at Publisher · View at Google Scholar · View at PubMed
  87. F. Podesta, G. Romeo, and W.-H. Liu et al., “Bax is increased in the retina of diabetic subjects and is associated with pericyte apoptosis in vivo and in vitro,” American Journal of Pathology, vol. 156, no. 3, pp. 1025–1032, 2000.
  88. A. J. Barber, E. Lieth, S. A. Khin, D. A. Antonetti, A. G. Buchanan, and T. W. Gardner, “Neural apoptosis in the retina during experimental and human diabetes: early onset and effect of insulin,” Journal of Clinical Investigation, vol. 102, no. 4, pp. 783–791, 1998.
  89. M. Mizutani, C. Gerhardinger, and M. Lorenzi, “Muller cell changes in human diabetic retinopathy,” Diabetes, vol. 47, no. 3, pp. 445–449, 1998.
  90. J. A. Phipps, E. L. Fletcher, and A. J. Vingrys, “Paired-flash identification of rod and cone dysfunction in the diabetic rat,” Investigative Ophthalmology & Visual Science, vol. 45, no. 12, pp. 4592–4600, 2004. View at Publisher · View at Google Scholar · View at PubMed
  91. T. Matsura, M. Kai, Y. Fujii, H. Ito, and K. Yamada, “Hydrogen peroxide-induced apoptosis in HL-60 cells requires caspase-3 activation,” Free Radical Research, vol. 30, no. 1, pp. 73–83, 1999. View at Publisher · View at Google Scholar
  92. H. Kaneto, Y. Kajimoto, and J. Miyagawa et al., “Beneficial effects of antioxidants in diabetes: possible protection of pancreatic β-cells against glucose toxicity,” Diabetes, vol. 48, no. 12, pp. 2398–2406, 1999.
  93. J. T. Hancock, R. Desikan, and S. J. Neill, “Does the redox status of cytochrome C act as a fail-safe mechanism in the regulation of programmed cell death?,” Free Radical Biology and Medicine, vol. 31, no. 5, pp. 697–703, 2001. View at Publisher · View at Google Scholar
  94. W. Li, M. Yanoff, B. Jian, and Z. He, “Altered mRNA levels of antioxidant enzymes in pre-apoptotic pericytes from human diabetic retinas,” Cellular and Molecular Biology, vol. 45, no. 1, pp. 59–66, 1999.
  95. C. D. Anuradha, S. Kanno, and S. Hirano, “Oxidative damage to mitochondria is a preliminary step to caspase-3 activation in fluoride-induced apoptosis in HL-60 cells,” Free Radical Biology and Medicine, vol. 31, no. 3, pp. 367–373, 2001. View at Publisher · View at Google Scholar
  96. S. Phaneuf and C. Leeuwenburgh, “Cytochrome c release from mitochondria in the aging heart: a possible mechanism for apoptosis with age,” American Journal of Physiology - Regulatory Integrative and Comparative Physiology, vol. 282, no. 2, pp. R423–R430, 2002.
  97. E. S. Alnemri, “Mammalian cell death proteases: a family of highly conserved aspartate specific cysteine proteases,” Journal of Cellular Biochemistry, vol. 64, no. 1, pp. 33–42, 1997. View at Publisher · View at Google Scholar
  98. S. Mohr, B. Zech, E. G. Lapetina, and B. Brüne, “Inhibition of caspase-3 by S-Nitrosation and oxidation caused by nitric oxide,” Biochemical and Biophysical Research Communications, vol. 238, no. 2, pp. 387–391, 1997. View at Publisher · View at Google Scholar · View at PubMed
  99. B. S. Kristal, S. J. Koopmans, C. T. Jackson, Y. Ikeno, B.-J. Park, and B. P. Yu, “Oxidant-mediated repression of mitochondrial transcription in diabetic rats,” Free Radical Biology and Medicine, vol. 22, no. 5, pp. 813–822, 1997. View at Publisher · View at Google Scholar
  100. X. Du, K. Stockklauser-Färber, and P. Rösen, “Generation of reactive oxygen intermediates, activation of NF-κB, and induction of apoptosis in human endothelial cells by glucose: role of nitric oxide synthase?,” Free Radical Biology and Medicine, vol. 27, no. 7-8, pp. 752–763, 1999. View at Publisher · View at Google Scholar
  101. G. Romeo, W.-H. Liu, V. Asnaghi, T. S. Kern, and M. Lorenzi, “Activation of nuclear factor-κB induced by diabetes and high glucose regulates a proapoptotic program in retinal pericytes,” Diabetes, vol. 51, no. 7, pp. 2241–2248, 2002.
  102. J. M. Griscavage, S. Wilk, and L. J. Ignarro, “Inhibitors of the proteasome pathway interfere with induction of nitric oxide synthase in macrophages by blocking activation of transcription factor NF-κB,” Proceedings of the National Academy of Sciences of the United States of America, vol. 93, no. 8, pp. 3308–3312, 1996. View at Publisher · View at Google Scholar
  103. J. S. Beckman and W. H. Koppenol, “Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and the ugly,” American Journal of Physiology - Cell Physiology, vol. 271, no. 5 part 1, pp. C1424–C1437, 1996.
  104. F. F. Behar-Cohen, S. Heydolph, V. Faure, M.-T. Droy-Lefaix, Y. Courtois, and O. Goureau, “Peroxynitrite cytotoxicity on bovine retinal pigmented epithelial cells in culture,” Biochemical and Biophysical Research Communications, vol. 226, no. 3, pp. 842–849, 1996. View at Publisher · View at Google Scholar · View at PubMed
  105. R. Radi, A. Cassina, R. Hodara, C. Quijano, and L. Castro, “Peroxynitrite reactions and formation in mitochondria,” Free Radical Biology and Medicine, vol. 33, no. 11, pp. 1451–1464, 2002. View at Publisher · View at Google Scholar
  106. R. A. Kowluru, S. Chakrabarti, and S. Chen, “Re-institution of good metabolic control in diabetic rats and activation of caspase-3 and nuclear transcriptional factor (NF-kB) in the retina,” Acta Diabetologica, vol. 41, no. 4, pp. 194–199, 2004. View at Publisher · View at Google Scholar · View at PubMed
  107. Y. Du, M. A. Smith, C. M. Miller, and T. S. Kern, “Diabetes-induced nitrative stress in the retina, and correction by aminoguanidine,” Journal of Neurochemistry, vol. 80, no. 5, pp. 771–779, 2002. View at Publisher · View at Google Scholar
  108. A. M. Joussen, T. Murata, A. Tsujikawa, B. Kirchhof, S.-E. Bursell, and A. P. Adamis, “Leukocyte-mediated endothelial cell injury and death in the diabetic retina,” American Journal of Pathology, vol. 158, no. 1, pp. 147–152, 2001.
  109. C. K. Chang and J. LoCicero III, “Overexpressed nuclear factor κB correlates with enhanced expression of interleukin-1β and inducible nitric oxide synthase in aged murine lungs to endotoxic stress,” Annals of Thoracic Surgery, vol. 77, no. 4, pp. 1222–1227, 2004. View at Publisher · View at Google Scholar · View at PubMed
  110. N. Quan, L. He, and W. Lai, “Endothelial activation is an intermediate step for peripheral lipopolysaccharide induced activation of paraventricular nucleus,” Brain Research Bulletin, vol. 59, no. 6, pp. 447–452, 2003. View at Publisher · View at Google Scholar
  111. R. Schreck, K. Albermann, and P. A. Baeuerle, “Nuclear factor κβ: an oxidative stress-responsive transcription factor of eukaryotic cells (a review),” Free Radical Research Communications, vol. 17, no. 4, pp. 221–237, 1992.
  112. T. Yuuki, T. Kanda, and Y. Kimura et al., “Inflammatory cytokines in vitreous fluid and serum of patients with diabetic vitreoretinopathy,” Journal of Diabetes and Its Complications, vol. 15, no. 5, pp. 257–259, 2001. View at Publisher · View at Google Scholar
  113. A. Carmo, J. G. Cunha-Vaz, A. P. Carvalho, and M. C. Lopes, “L-arginine transport in retinas from streptozotocin diabetic rats: correlation with the level of IL-1β and NO synthase activity,” Vision Research, vol. 39, no. 23, pp. 3817–3823, 1999. View at Publisher · View at Google Scholar
  114. R. A. Kowluru and S. Odenbach, “Role of interleukin-1β in the pathogenesis of diabetic retinopathy,” British Journal of Ophthalmology, vol. 88, no. 10, pp. 1343–1347, 2004. View at Publisher · View at Google Scholar · View at PubMed
  115. T. Vassilakopoulos, M.-H. Karatza, P. Katsaounou, A. Kollintza, S. Zakynthinos, and C. Roussos, “Antioxidants attenuate the plasma cytokine response to exercise in humans,” Journal of Applied Physiology, vol. 94, no. 3, pp. 1025–1032, 2003.
  116. R. A. Kowluru and S. Odenbach, “Role of interleukin-1β in the development of retinopathy in rats: effect of antioxidants,” Investigative Ophthalmology & Visual Science, vol. 45, no. 11, pp. 4161–4166, 2004. View at Publisher · View at Google Scholar · View at PubMed
  117. J. L. Wilkinson-Berka, “Vasoactive factors and diabetic retinopathy: vascular endothelial growth factor, cycoloxygenase-2 and nitric oxide,” Current Pharmaceutical Design, vol. 10, no. 27, pp. 3331–3348, 2004. View at Publisher · View at Google Scholar
  118. L. Packer, E. H. Witt, and H. J. Tritschler, “Alpha-lipoic acid as a biological antioxidant,” Free Radical Biology and Medicine, vol. 19, no. 2, pp. 227–250, 1995. View at Publisher · View at Google Scholar
  119. J. Lin, A. Bierhaus, and P. Bugert et al., “Effect of R-(+)-α-lipoic acid on experimental diabetic retinopathy,” Diabetologia, vol. 49, no. 5, pp. 1089–1096, 2006. View at Publisher · View at Google Scholar · View at PubMed
  120. I. G. Obrosova, L. Fathallah, E. Liu, and J. Nourooz-Zadeh, “Early oxidative stress in the diabetic kidney: effect of DL-α-lipoic acid,” Free Radical Biology and Medicine, vol. 34, no. 2, pp. 186–195, 2003. View at Publisher · View at Google Scholar
  121. H.-P. Hammes, X. Du, and D. Edelstein et al., “Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy,” Nature Medicine, vol. 9, no. 3, pp. 294–299, 2003. View at Publisher · View at Google Scholar · View at PubMed
  122. M. C. Sabu, K. Smitha, and R. Kuttan, “Anti-diabetic activity of green tea polyphenols and their role in reducing oxidative stress in experimental diabetes,” Journal of Ethnopharmacology, vol. 83, no. 1-2, pp. 109–116, 2002. View at Publisher · View at Google Scholar
  123. G. T. Mustata, M. Rosca, and K. M. Biemel et al., “Paradoxical effects of green tea (Camellia sinensis) and antioxidant vitamins in diabetic rats: improved retinopathy and renal mitochondrial defects but deterioration of collagen matrix glycoxidation and cross-linking,” Diabetes, vol. 54, no. 2, pp. 517–526, 2005.
  124. N. H. Ansari, W. Zhang, E. Fulep, and A. Mansour, “Prevention of pericyte loss by Trolox in diabetic rat retina,” Journal of Toxicology and Environmental Health—Part A, vol. 54, no. 6, pp. 467–475, 1998.
  125. H. P. Hammes, A. Bartmann, L. Engel, and P. Wülfroth, “Antioxidant treatment of experimental diabetic retinopathy in rats with nicanartine,” Diabetologia, vol. 40, no. 6, pp. 629–634, 1997. View at Publisher · View at Google Scholar
  126. S. A. Moustafa, “Zinc might protect oxidative changes in the retina and pancreas at the early stage of diabetic rats,” Toxicology and Applied Pharmacology, vol. 201, no. 2, pp. 149–155, 2004. View at Publisher · View at Google Scholar · View at PubMed
  127. M. F. McCarty, “The putative therapeutic value of high-dose selenium in proliferative retinopathies may reflect down-regulation of VEGF production by the hypoxic retina,” Medical Hypotheses, vol. 64, no. 1, pp. 159–161, 2005. View at Publisher · View at Google Scholar · View at PubMed
  128. R. A. Kowluru, R. L. Engerman, and T. S. Kern, “Abnormalities of retinal metabolism in diabetes or experimental galactosemia. VI. Comparison of retinal and cerebral cortex metabolism, and effects of antioxidant therapy,” Free Radical Biology and Medicine, vol. 26, no. 3-4, pp. 371–378, 1999. View at Publisher · View at Google Scholar
  129. R. P. Garay, P. Hannaert, and C. Chiavaroli, “Calcium dobesilate in the treatment of diabetic retinopathy,” Treatments in Endocrinology, vol. 4, no. 4, pp. 221–232, 2005. View at Publisher · View at Google Scholar
  130. L. Spadea and E. Balestrazzi, “Treatment of vascular retinopathies with Pycnogenol,” Phytotherapy Research, vol. 15, no. 3, pp. 219–223, 2001. View at Publisher · View at Google Scholar · View at PubMed
  131. S.-E. Bursell, A. C. Clermont, and L. P. Aiello et al., “High-dose vitamin E supplementation normalizes retinal blood flow and creatinine clearance in patients with type 1 diabetes,” Diabetes Care, vol. 22, no. 8, pp. 1245–1251, 1999.
  132. A. E. Millen, M. Gruber, R. Klein, B. E. K. Klein, M. Palta, and J. A. Mares, “Relations of serum ascorbic acid and α-tocopherol to diabetic retinopathy in the Third National Health and Nutrition Examination Survey,” American Journal of Epidemiology, vol. 158, no. 3, pp. 225–233, 2003. View at Publisher · View at Google Scholar
  133. A. E. Millen, R. Klein, A. R. Folsom, J. Stevens, M. Palta, and J. A. Mares, “Relation between intake of vitamins C and E and risk of diabetic retinopathy in the Atherosclerosis Risk in Communities Study,” American Journal of Clinical Nutrition, vol. 79, no. 5, pp. 865–873, 2004.
  134. E. J. Mayer-Davis, R. A. Bell, B. A. Reboussin, J. Rushing, J. A. Marshall, and R. F. Hamman, “Antioxidant nutrient intake and diabetic retinopathy: the San Luis Valley diabetes study,” Ophthalmology, vol. 105, no. 12, pp. 2264–2270, 1998. View at Publisher · View at Google Scholar