Table of Contents Author Guidelines Submit a Manuscript
Experimental Diabetes Research
Volume 2007, Article ID 31867, 12 pages
http://dx.doi.org/10.1155/2007/31867
Review Article

Cellular Signaling and Potential New Treatment Targets in Diabetic Retinopathy

Department of Pathology, University of Western Ontario, London, Ontario, Canada N6A 5C1

Received 28 December 2006; Revised 2 May 2007; Accepted 13 September 2007

Academic Editor: Timothy Kern

Copyright © 2007 Zia A. Khan and Subrata Chakrabarti. 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. F. I. Caird, “The epidemiology of diabetic microangiopathy,” Acta Diabetologica Latina, vol. 8, supplement 1, pp. 240–248, 1971.
  2. R. S. Mazze, P. Sinnock, L. Deeb, and J. L. Brimberry, “An epidemiological model for diabetes mellitus in the United States: five major complications,” Diabetes Research and Clinical Practice, vol. 1, no. 3, pp. 185–191, 1985. View at Publisher · View at Google Scholar
  3. D. S. Fong, L. Aiello, and T. W. Gardner et al., “Diabetic retinopathy,” Diabetes Care, vol. 26, pp. 226–229, 2003. View at Publisher · View at Google Scholar
  4. V. A. Alder, E. N. Su, D. Y. Yu, S. J. Cringle, and P. K. Yu, “Diabetic retinopathy: early functional changes,” Clinical and Experimental Pharmacology and Physiology, vol. 24, no. 9-10, pp. 785–788, 1997. View at Publisher · View at Google Scholar
  5. M. D. Davis, “Diabetic retinopathy. A clinical overview,” Diabetes Care, vol. 15, no. 12, pp. 1844–1874, 1992. View at Publisher · View at Google Scholar
  6. C. Hudson, “The clinical features and classification of diabetic retinopathy,” Ophthalmic and Physiological Optics, vol. 16, supplement 2, pp. 43–48, 1996. View at Publisher · View at Google Scholar
  7. K. A. Neely, D. A. Quillen, A. P. Schachat, T. W. Gardner, and G. W. Blankenship, “Diabetic retinopathy,” The Medical Clinics of North America, vol. 82, no. 4, pp. 847–876, 1998. View at Publisher · View at Google Scholar
  8. F. C. Piccolino, M. Zingirian, and C. Mosci, “Classification of proliferative diabetic retinopathy,” Graefe's Archive for Clinical and Experimental Ophthalmology, vol. 225, no. 4, pp. 245–250, 1987. View at Publisher · View at Google Scholar
  9. H. F. Spalter, “Diabetic maculopathy,” Metabolic, Pediatric and Systemic Ophthalmology, vol. 7, no. 4, pp. 211–215, 1983.
  10. H. Shamoon, H. Duffy, and N. Fleischer et al., “The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus,” New England Journal of Medicine, vol. 329, no. 14, pp. 977–986, 1993. View at Publisher · View at Google Scholar
  11. UK Prospective Diabetes Study (UKPDS) Group, “Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34),” The Lancet, vol. 352, no. 9131, pp. 854–865, 1998. View at Publisher · View at Google Scholar
  12. 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
  13. Z. A. Khan and S. Chakrabarti, “Endothelins in chronic diabetic complications,” Canadian Journal of Physiology and Pharmacology, vol. 81, no. 6, pp. 622–634, 2003. View at Publisher · View at Google Scholar · View at PubMed
  14. M. A. van de Ree, M. V. Huisman, F. H. de Man, J. C. van der Vijver, A. E. Meinders, and G. J. Blauw, “Impaired endothelium-dependent vasodilation in type 2 diabetes mellitus and the lack of effect of simvastatin,” Cardiovascular Research, vol. 52, no. 2, pp. 299–305, 2001. View at Publisher · View at Google Scholar
  15. G. Dogra, L. Rich, K. Stanton, and G. F. Watts, “Endothelium-dependent and independent vasodilation studied at normoglycaemia in type I diabetes mellitus with and without microalbuminuria,” Diabetologia, vol. 44, no. 5, pp. 593–601, 2001. View at Publisher · View at Google Scholar
  16. J. Lambert, M. Aarsen, A. J. Donker, and C. D. Stehouwer, “Endothelium-dependent and -independent vasodilation of large arteries in normoalbuminuric insulin-dependent diabetes mellitus,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 16, no. 5, pp. 705–711, 1996.
  17. M. T. Johnstone, S. J. Creager, K. M. Scales, J. A. Cusco, B. K. Lee, and M. A. Creager, “Impaired endothelium-dependent vasodilation in patients with insulin- dependent diabetes mellitus,” Circulation, vol. 88, no. 6, pp. 2510–2516, 1993.
  18. G. E. McVeigh, G. M. Brennan, and G. D. Johnston et al., “Impaired endothelium-dependent and independent vasodilation in patients with type 2 (non-insulin-dependent) diabetes mellitus,” Diabetologia, vol. 35, no. 8, pp. 771–776, 1992. View at Publisher · View at Google Scholar
  19. D. Deng, T. Evans, K. Mukherjee, D. Downey, and S. Chakrabarti, “Diabetes-induced vascular dysfunction in the retina: role of endothelins,” Diabetologia, vol. 42, no. 10, pp. 1228–1234, 1999. View at Publisher · View at Google Scholar
  20. M. Cukiernik, S. Mukherjee, D. Downey, and S. Chakabarti, “Heme oxygenase in the retina in diabetes,” Current Eye Research, vol. 27, no. 5, pp. 301–308, 2003. View at Publisher · View at Google Scholar
  21. S. Chen, Z. A. Khan, M. Cukiernik, and S. Chakrabarti, “Differential activation of NF-κB and AP-1 in increased fibronectin synthesis in target organs of diabetic complications,” American Journal of Physiology. Endocrinology and Metabolism, vol. 284, pp. E1089–E1097, 2003.
  22. Z. A. Khan, B. M. Chan, and S. Uniyal et al., “EDB fibronectin and angiogenesis—a novel mechanistic pathway,” Angiogenesis, vol. 8, no. 3, pp. 183–196, 2005. View at Publisher · View at Google Scholar · View at PubMed
  23. X. Xin, Z. A. Khan, S. Chen, and S. Chakrabarti, “Extracellular signal-regulated kinase (ERK) in glucose-induced and endothelin-mediated fibronectin synthesis,” Laboratory Investigation, vol. 84, pp. 1451–1459, 2004. View at Publisher · View at Google Scholar · View at PubMed
  24. S. Chen, M. D. Apostolova, M. G. Cherian, and S. Chakrabarti, “Interaction of endothelin-1 with vasoactive factors in mediating glucose-induced increased permeability in endothelial cells,” Laboratory Investigation, vol. 80, no. 8, pp. 1311–1321, 2000.
  25. S. Chen, Z. A. Khan, Y. Barbin, and S. Chakrabarti, “Pro-oxidant role of heme oxygenase in mediating glucose-induced endothelial cell damage,” Free Radical Research, vol. 38, no. 12, pp. 1301–1310, 2004. View at Publisher · View at Google Scholar · View at PubMed
  26. Z. A. Khan, H. Farhangkhoee, and S. Chakrabarti, “Towards newer molecular targets for chronic diabetic complications,” Current Vascular Pharmacology, vol. 4, no. 1, pp. 45–57, 2006. View at Publisher · View at Google Scholar
  27. H. Farhangkhoee, Z. A. Khan, and S. Mukherjee et al., “Heme oxygenase in diabetes-induced oxidative stress in the heart,” Journal of Molecular and Cellular Cardiology, vol. 35, no. 12, pp. 1439–1448, 2003. View at Publisher · View at Google Scholar
  28. D. S. Gelinas, P. N. Bernatchez, S. Rollin, N. G. Bazan, and M. G. Sirois, “Immediate and delayed VEGF-mediated NO synthesis in endothelial cells: role of PI3K, PKC and PLC pathways,” British Journal of Pharmacology, vol. 137, no. 7, pp. 1021–1030, 2002. View at Publisher · View at Google Scholar · View at PubMed
  29. R. S. Scotland, M. Morales-Ruiz, and Y. Chen et al., “Functional reconstitution of endothelial nitric oxide synthase reveals the importance of serine 1179 in endothelium-dependent vasomotion,” Circulation Research, vol. 90, no. 8, pp. 904–910, 2002. View at Publisher · View at Google Scholar
  30. S. Dimmeler, I. Fleming, B. Fisslthaler, C. Hermann, R. Busse, and A. M. Zeiher, “Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation,” Nature, vol. 399, no. 6736, pp. 601–605, 1999. View at Publisher · View at Google Scholar · View at PubMed
  31. S. W. Ryter and R. M. Tyrrell, “The heme synthesis and degradation pathways: role in oxidant sensitivity. Heme oxygenase has both pro- and antioxidant properties,” Free Radical Biology and Medicine, vol. 28, no. 2, pp. 289–309, 2000. View at Publisher · View at Google Scholar
  32. D. B. Archer, “Bowman lecture 1998. Diabetic retinopathy: some cellular, molecular and therapeutic considerations,” Eye, vol. 13, part 4, pp. 497–523, 1999.
  33. M. Lorenzi and C. Gerhardinger, “Early cellular and molecular changes induced by diabetes in the retina,” Diabetologia, vol. 44, no. 7, pp. 791–804, 2001. View at Publisher · View at Google Scholar
  34. S. S. Feman, “The natural history of the first clinically visible features of diabetic retinopathy,” Transactions of the American Ophthalmological Society, vol. 92, pp. 745–773, 1994.
  35. M. A. Attawia and R. C. Nayak, “Circulating antipericyte autoantibodies in diabetic retinopathy,” Retina, vol. 19, no. 5, pp. 390–400, 1999. View at Publisher · View at Google Scholar
  36. R. C. Nayak, C. D. Agardh, M. G. Kwok, H. Stjernquist, P. J. Farthing-Nayak, and E. Agardh, “Circulating anti-pericyte autoantibodies are present in type 2 diabetic patients and are associated with non-proliferative retinopathy,” Diabetologia, vol. 46, no. 4, pp. 511–513, 2003.
  37. G. Allt and J. G. Lawrenson, “Pericytes: cell biology and pathology,” Cells Tissues Organs, vol. 169, no. 1, pp. 1–11, 2001. View at Publisher · View at Google Scholar
  38. P. M. Newcomb and I. M. Herman, “Pericyte growth and contractile phenotype: modulation by endothelial-synthesized matrix and comparison with aortic smooth muscle,” Journal of Cellular Physiology, vol. 155, no. 2, pp. 385–393, 1993. View at Publisher · View at Google Scholar · View at PubMed
  39. D. Ruggiero, M. Lecomte, E. Michoud, M. Lagarde, and N. Wiernsperger, “Involvement of cell-cell interactions in the pathogenesis of diabetic retinopathy,” Diabetes & Metabolism, vol. 23, no. 1, pp. 30–42, 1997.
  40. Z. A. Khan and S. Chakrabarti, “Growth factors in proliferative diabetic retinopathy,” Experimental Diabesity Research, vol. 4, no. 4, pp. 287–301, 2003.
  41. C. K. Chee and D. W. Flanagan, “Visual field loss with capillary non-perfusion in preproliferative and early proliferative diabetic retinopathy,” British Journal of Ophthalmology, vol. 77, no. 11, pp. 726–730, 1993. View at Publisher · View at Google Scholar
  42. E. M. Kohner and P. Henkind, “Correlation of fluorescein angiogram and retinal digest in diabetic retinopathy,” American Journal of Ophthalmology, vol. 69, no. 3, pp. 403–414, 1970.
  43. H. P. Hammes, J. Lin, and O. Renner et al., “Pericytes and the pathogenesis of diabetic retinopathy,” Diabetes, vol. 51, no. 10, pp. 3107–3112, 2002. View at Publisher · View at Google Scholar
  44. M. Murata, N. Ohta, and S. Fujisawa et al., “Selective pericyte degeneration in the retinal capillaries of galactose-fed dogs results from apoptosis linked to aldose reductase-catalyzed galactitol accumulation,” Journal of Diabetes and Its Complications, vol. 16, no. 5, pp. 363–370, 2002. View at Publisher · View at Google Scholar
  45. J. Cai and M. Boulton, “The pathogenesis of diabetic retinopathy: old concepts and new questions,” Eye, vol. 16, no. 3, pp. 242–260, 2002. View at Publisher · View at Google Scholar
  46. T. A. Ciulla, A. Harris, and P. Latkany et al., “Ocular perfusion abnormalities in diabetes,” Acta Ophthalmologica Scandinavica, vol. 80, no. 5, pp. 468–477, 2002. View at Publisher · View at Google Scholar
  47. J. A. Colwell, P. D. Winocour, and P. V. Halushka, “Do platelets have anything to do with diabetic microvascular disease?,” Diabetes, vol. 32, supplement 2, pp. 14–19, 1983.
  48. K. Yamashiro, A. Tsujikawa, and S. Ishida et al., “Platelets accumulate in the diabetic retinal vasculature following endothelial death and suppress blood-retinal barrier breakdown,” American Journal of Pathology, vol. 163, no. 1, pp. 253–259, 2003.
  49. W. Sun, C. Gerhardinger, Z. Dagher, T. Hoehn, and M. Lorenzi, “Aspirin at low-intermediate concentrations protects retinal vessels in experimental diabetic retinopathy through non-platelet-mediated effects,” Diabetes, vol. 54, no. 12, pp. 3418–3426, 2005. View at Publisher · View at Google Scholar
  50. M. Matsuoka, N. Ogata, K. Minamino, and M. Matsumura, “Leukostasis and pigment epithelium-derived factor in rat models of diabetic retinopathy,” Molecular Vision, vol. 13, pp. 1058–1065, 2007.
  51. S. Schroder, W. Palinski, and G. W. Schmid-Schonbein, “Activated monocytes and granulocytes, capillary nonperfusion, and neovascularization in diabetic retinopathy,” American Journal of Pathology, vol. 139, no. 1, pp. 81–100, 1991.
  52. J. M. Hughes, A. Brink, A. N. Witmer, M. Hanraads-de Riemer, I. Klaassen, and R. O. Schlingemann, “Vascular leucocyte adhesion molecules unaltered in the human retina in diabetes,” British Journal of Ophthalmology, vol. 88, no. 4, pp. 566–572, 2004. View at Publisher · View at Google Scholar
  53. D. S. McLeod, D. J. Lefer, C. Merges, and G. A. Lutty, “Enhanced expression of intracellular adhesion molecule-1 and P-selectin in the diabetic human retina and choroid,” American Journal of Pathology, vol. 147, no. 3, pp. 642–653, 1995.
  54. G. A. Limb, J. Hickman-Casey, R. D. Hollifield, and A. H. Chignell, “Vascular adhesion molecules in vitreous from eyes with proliferative diabetic retinopathy,” Investigative Ophthalmology & Visual Science, vol. 40, no. 10, pp. 2453–2457, 1999.
  55. A. M. Schmidt, O. Hori, and J. X. Chen et al., “Advanced glycation endproducts interacting with their endothelial receptor induce expression of vascular cell adhesion molecule-1 (VCAM-1) in cultured human endothelial cells and in mice. A potential mechanism for the accelerated vasculopathy of diabetes,” Journal of Clinical Investigation, vol. 96, pp. 1395–1403, 1995.
  56. D. A. Antonetti, E. Lieth, A. J. Barber, and T. W. Gardner, “Molecular mechanisms of vascular permeability in diabetic retinopathy,” Seminars in Ophthalmology, vol. 14, no. 4, pp. 240–248, 1999.
  57. I. H. Wallow and R. L. Engerman, “Permeability and patency of retinal blood vessels in experimental diabetes,” Investigative Ophthalmology & Visual Science, vol. 16, no. 5, pp. 447–461, 1977.
  58. A. Castillo, J. M. Benitez Del Castillo, D. Diaz, O. Sayagues, J. L. Ruibal, and J. Garcia-Sanchez, “Analysis of the blood-retinal barrier: its relation to clinical and metabolic factors and progression to retinopathy in juvenile diabetics. A 4-year follow-up study,” Graefe's Archive for Clinical and Experimental Ophthalmology, vol. 234, no. 4, pp. 246–250, 1996. View at Publisher · View at Google Scholar
  59. J. Cunha-Vaz, C. Lobo, J. Castro Sousa, B. Oliveiros, E. Leite, and J. R. Faria de Abreu, “Progression of retinopathy and alteration of the blood-retinal barrier in patients with type 2 diabetes: a 7-year prospective follow-up study,” Graefe's Archive for Clinical and Experimental Ophthalmology, vol. 236, no. 4, pp. 264–268, 1998. View at Publisher · View at Google Scholar
  60. L. Kessel, B. Moldow, J. A. van Best, and B. Sander, “Corneal autofluorescence in relation to permeability of the blood-aqueous barrier in diabetic patients with clinically significant macular edema and in an age-matched control group,” Current Eye Research, vol. 26, no. 5, pp. 307–312, 2003. View at Publisher · View at Google Scholar
  61. C. L. Lobo, R. C. Bernardes, J. R. Faria de Abreu, and J. G. Cunha-Vaz, “One-year follow-up of blood-retinal barrier and retinal thickness alterations in patients with type 2 diabetes mellitus and mild nonproliferative retinopathy,” Archives of Ophthalmology, vol. 119, no. 10, pp. 1469–1474, 2001.
  62. C. L. Lobo, R. C. Bernardes, J. P. Figueira, J. R. Faria de Abreu, and J. G. Cunha-Vaz, “Three-year follow-up study of blood-retinal barrier and retinal thickness alterations in patients with type 2 diabetes mellitus and mild nonproliferative diabetic retinopathy,” Archives of Ophthalmology, vol. 122, no. 2, pp. 211–217, 2004. View at Publisher · View at Google Scholar · View at PubMed
  63. B. Sander, M. Larsen, C. Engler, H. Lund-Andersen, and H. H. Parving, “Early changes in diabetic retinopathy: capillary loss and blood-retina barrier permeability in relation to metabolic control,” Acta Ophthalmologica, vol. 72, no. 5, pp. 553–559, 1994.
  64. R. Schalnus and C. Ohrloff, “The blood-ocular barrier in type I diabetes without diabetic retinopathy: permeability measurements using fluorophotometry,” Ophthalmic Research, vol. 27, supplement 1, pp. 116–123, 1995.
  65. R. Schalnus, C. Ohrloff, E. Jungmann, K. Maass, S. Rinke, and A. Wagner, “Permeability of the blood-retinal barrier and the blood-aqueous barrier in type I diabetes without diabetic retinopathy: simultaneous evaluation with fluorophotometry,” German journal of ophthalmology, vol. 2, no. 4-5, pp. 202–206, 1993.
  66. S. Roy and M. Lorenzi, “Early biosynthetic changes in the diabetic-like retinopathy of galactose-fed rats,” Diabetologia, vol. 39, no. 6, pp. 735–738, 1996. View at Publisher · View at Google Scholar
  67. S. Roy, M. Maiello, and M. Lorenzi, “Increased expression of basement membrane collagen in human diabetic retinopathy,” Journal of Clinical Investigation, vol. 93, no. 1, pp. 438–442, 1994.
  68. S. Roy and T. Sate, “Role of vascular basement membrane components in diabetic microangiopathy,” Drug News and Perspectives, vol. 13, no. 2, pp. 91–98, 2000. View at Publisher · View at Google Scholar
  69. S. Roy, T. Sato, G. Paryani, and R. Kao, “Downregulation of fibronectin overexpression reduces basement membrane thickening and vascular lesions in retinas of galactose-fed rats,” Diabetes, vol. 52, no. 5, pp. 1229–1234, 2003. View at Publisher · View at Google Scholar
  70. M. D. Siperstein, R. H. Unger, and L. L. Madison, “Studies of muscle capillary basement membranes in normal subjects, diabetic, and prediabetic patients,” Journal of Clinical Investigation, vol. 47, no. 9, pp. 1973–1999, 1968.
  71. T. Yamashita and B. Becker, “The basement membrane in the human diabetic eye,” Diabetes, vol. 10, pp. 167–174, 1961.
  72. E. Cagliero, M. Maiello, D. Boeri, S. Roy, and M. Lorenzi, “Increased expression of basement membrane components in human endothelial cells cultured in high glucose,” Journal of Clinical Investigation, vol. 82, no. 2, pp. 735–738, 1988.
  73. E. Cagliero, T. Roth, S. Roy, and M. Lorenzi, “Characteristics and mechanisms of high-glucose-induced overexpression of basement membrane components in cultured human endothelial cells,” Diabetes, vol. 40, no. 1, pp. 102–110, 1991. View at Publisher · View at Google Scholar
  74. H. Hua, H. J. Goldberg, I. G. Fantus, and C. I. Whiteside, “High glucose-enhanced mesangial cell extracellular signal-regulated protein kinase activation and α1(IV) collagen expression in response to endothelin-1: role of specific protein kinase C isozymes,” Diabetes, vol. 50, no. 10, pp. 2376–2383, 2001. View at Publisher · View at Google Scholar
  75. T. Nishikawa, I. Giardino, D. Edelstein, and M. Brownlee, “Changes in diabetic retinal matrix protein mRNA levels in a common transgenic mouse strain,” Current Eye Research, vol. 21, no. 1, pp. 581–587, 2000. View at Publisher · View at Google Scholar
  76. S. Chen, T. Evans, K. Mukherjee, M. Karmazyn, and S. Chakrabarti, “Diabetes-induced myocardial structural changes: Role of endothelin-1 and its receptors,” Journal of Molecular and Cellular Cardiology, vol. 32, no. 9, pp. 1621–1629, 2000. View at Publisher · View at Google Scholar · View at PubMed
  77. T. Evans, D. X. Deng, S. Chen, and S. Chakrabarti, “Endothelin receptor blockade prevents augmented extracellular matrix component mRNA expression and capillary basement membrane thickening in the retina of diabetic and galactose-fed rats,” Diabetes, vol. 49, no. 4, pp. 662–666, 2000. View at Publisher · View at Google Scholar
  78. A. V. Ljubimov, R. E. Burgeson, and R. J. Butkowski et al., “Basement membrane abnormalities in human eyes with diabetic retinopathy,” Journal of Histochemistry and Cytochemistry, vol. 44, no. 12, pp. 1469–1479, 1996.
  79. K. S. Spirin, M. Saghizadeh, S. L. Lewin, L. Zardi, M. C. Kenney, and A. V. Ljubimov, “Basement membrane and growth factor gene expression in normal and diabetic human retinas,” Current Eye Research, vol. 18, no. 6, pp. 490–499, 1999. View at Publisher · View at Google Scholar
  80. A. N. Witmer, J. van den Born, G. F. Vrensen, and R. O. Schlingemann, “Vascular localization of heparan sulfate proteoglycans in retinas of patients with diabetes mellitus and in VEGF-induced retinopathy using domain-specific antibodies,” Current Eye Research, vol. 22, no. 3, pp. 190–197, 2001. View at Publisher · View at Google Scholar
  81. Z. A. Khan, M. Cukiernik, J. R. Gonder, and S. Chakrabarti, “Oncofetal fibronectin in diabetic retinopathy,” Investigative Ophthalmology & Visual Science, vol. 45, no. 1, pp. 287–295, 2004. View at Publisher · View at Google Scholar
  82. C. G. Schalkwijk and C. D. Stehouwer, “Vascular complications in diabetes mellitus: the role of endothelial dysfunction,” Clinical Science, vol. 109, no. 2, pp. 143–159, 2005. View at Publisher · View at Google Scholar · View at PubMed
  83. R. J. Boado and W. M. Pardridge, “The brain-type glucose transporter mRNA is specifically expressed at the blood-brain barrier,” Biochemical and Biophysical Research Communications, vol. 166, no. 1, pp. 174–179, 1990. View at Publisher · View at Google Scholar
  84. T. B. Choi, R. J. Boado, and W. M. Pardridge, “Blood-brain barrier glucose transporter mRNA is increased in experimental diabetes mellitus,” Biochemical and Biophysical Research Communications, vol. 164, no. 1, pp. 375–380, 1989. View at Publisher · View at Google Scholar
  85. J. H. Kinoshita and C. Nishimura, “The involvement of aldose reductase in diabetic complications,” Diabetes/Metabolism Reviews, vol. 4, no. 4, pp. 323–337, 1988.
  86. C. Yabe-Nishimura, “Aldose reductase in glucose toxicity: a potential target for the prevention of diabetic complications,” Pharmacological Reviews, vol. 50, no. 1, pp. 21–33, 1998.
  87. D. A. Greene, S. Chakrabarti, S. A. Lattimer, and A. A. Sima, “Role of sorbitol accumulation and myo-inositol depletion in paranodal swelling of large myelinated nerve fibers in the insulin-deficient spontaneously diabetic bio-breeding rat. Reversal by insulin replacement, an aldose reductase inhibitor, and myo-inositol,” Journal of Clinical Investigation, vol. 79, no. 5, pp. 1479–1485, 1987.
  88. S. Chakrabarti and A. A. Sima, “The effect of myo-inositol treatment on basement membrame thickening in the BB/W-rat retina,” Diabetes Research and Clinical Practice, vol. 16, no. 1, pp. 13–17, 1992. View at Publisher · View at Google Scholar
  89. N. Trueblood and R. Ramasamy, “Aldose reductase inhibition improves altered glucose metabolism of isolated diabetic rat hearts,” American Journal of Physiology. Heart and Circulatory Physiology, vol. 275, no. 1, part 2, pp. H75–H83, 1998.
  90. K. Sivenius, L. Niskanen, R. Voutilainen-Kaunisto, M. Laakso, and M. Uusitupa, “Aldose reductase gene polymorphisms and susceptibility to microvascular complications in type 2 diabetes,” Diabetic Medicine, vol. 21, no. 12, pp. 1325–1333, 2004. View at Publisher · View at Google Scholar · View at PubMed
  91. Y. Wang, M. C. Ng, and S. C. Lee et al., “Phenotypic heterogeneity and associations of two aldose reductase gene polymorphisms with nephropathy and retinopathy in type 2 diabetes,” Diabetes Care, vol. 26, no. 8, pp. 2410–2415, 2003. View at Publisher · View at Google Scholar
  92. A. G. Demaine, “Polymorphisms of the aldose reductase gene and susceptibility to diabetic microvascular complications,” Current Medicinal Chemistry, vol. 10, no. 15, pp. 1389–1398, 2003. View at Publisher · View at Google Scholar
  93. Sorbinil Retinopathy Trial Research Group, “A randomized trial of sorbinil, an aldose reductase inhibitor, in diabetic retinopathy,” Archives of Ophthalmology, vol. 108, no. 9, pp. 1234–1244, 1990.
  94. W. Sun, P. J. Oates, J. B. Coutcher, C. Gerhardinger, and M. Lorenzi, “A selective aldose reductase inhibitor of a new structural class prevents or reverses early retinal abnormalities in experimental diabetic retinopathy,” Diabetes, vol. 55, no. 10, pp. 2757–2762, 2006. View at Publisher · View at Google Scholar · View at PubMed
  95. S. P. Wolff, “Diabetes mellitus and free radicals. Free radicals, transition metals and oxidative stress in the aetiology of diabetes mellitus and complications,” British Medical Bulletin, vol. 49, no. 3, pp. 642–652, 1993.
  96. T. Nishikawa, D. Edelstein, and X. L. Du et al., “Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage,” Nature, vol. 404, no. 6779, pp. 787–790, 2000. View at Publisher · View at Google Scholar · View at PubMed
  97. 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
  98. A. M. Zafari, M. Ushio-Fukai, and M. Akers et al., “Role of NADH/NADPH oxidase-derived H2O2 in angiotensin II-induced vascular hypertrophy,” Hypertension, vol. 32, no. 3, pp. 488–495, 1998.
  99. A. Warnholtz, G. Nickenig, and E. Schulz et al., “Increased NADH-oxidase-mediated superoxide production in the early stages of atherosclerosis: evidence for involvement of the renin-angiotensin system,” Circulation, vol. 99, no. 15, pp. 2027–2033, 1999.
  100. H. Farhangkhoee, Z. A. Khan, Y. Barbin, and S. Chakrabarti, “Glucose-induced up-regulation of CD36 mediates oxidative stress and microvascular endothelial cell dysfunction,” Diabetologia, vol. 48, no. 7, pp. 1401–1410, 2005. View at Publisher · View at Google Scholar · View at PubMed
  101. S. Parthasarathy, E. Wieland, and D. Steinberg, “A role for endothelial cell lipoxygenase in the oxidative modification of low density lipoprotein,” Proceedings of the National Academy of Sciences of the United States of America, vol. 86, no. 3, pp. 1046–1050, 1989. View at Publisher · View at Google Scholar
  102. P. Decker and S. Muller, “Modulating poly (ADP-ribose) polymerase activity: potential for the prevention and therapy of pathogenic situations involving DNA damage and oxidative stress,” Current Pharmaceutical Biotechnology, vol. 3, no. 3, pp. 275–283, 2002. View at Publisher · View at Google Scholar
  103. I. G. Obrosova, P. Pacher, and C. Szabo et al., “Aldose reductase inhibition counteracts oxidative-nitrosative stress and poly(ADP-ribose) polymerase activation in tissue sites for diabetes complications,” Diabetes, vol. 54, no. 1, pp. 234–242, 2005. View at Publisher · View at Google Scholar
  104. H. Kaur, S. Chen, X. Xin, J. Chiu, Z. A. Khan, and S. Chakrabarti, “Diabetes-induced extracellular matrix protein expression is mediated by transcription coactivator p300,” Diabetes, vol. 55, no. 11, pp. 3104–3111, 2006. View at Publisher · View at Google Scholar · View at PubMed
  105. L. Zheng, C. Szabo, and T. S. Kern, “Poly(ADP-ribose) polymerase is involved in the development of diabetic retinopathy via regulation of nuclear factor-κB,” Diabetes, vol. 53, pp. 2960–2967, 2004. View at Publisher · View at Google Scholar
  106. P. O. Hassa, S. S. Haenni, and C. Buerki et al., “Acetylation of poly(ADP-ribose) polymerase-1 by p300/CREB-binding protein regulates coactivation of NF-κB-dependent transcription,” Journal of biological chemistry, vol. 280, no. 49, pp. 40450–40464, 2005. View at Publisher · View at Google Scholar · View at PubMed
  107. K. Ota, M. Kameoka, Y. Tanaka, A. Itaya, and K. Yoshihara, “Expression of histone acetyltransferases was down-regulated in poly(ADP-ribose) polymerase-1-deficient murine cells,” Biochemical and Biophysical Research Communications, vol. 310, no. 2, pp. 312–317, 2003. View at Publisher · View at Google Scholar
  108. H. Vlassara, “Recent progress in advanced glycation end products and diabetic complications,” Diabetes, vol. 46, supplement 2, pp. S19–S25, 1997.
  109. H. Vlassara, “The AGE-receptor in the pathogenesis of diabetic complications,” Diabetes/Metabolism Research and Reviews, vol. 17, no. 6, pp. 436–443, 2001. View at Publisher · View at Google Scholar · View at PubMed
  110. A. Bierhaus, M. A. Hofmann, R. Ziegler, and P. P. Nawroth, “AGEs and their interaction with AGE-receptors in vascular disease and diabetes mellitus. I. The AGE concept,” Cardiovascular Research, vol. 37, no. 3, pp. 586–600, 1998. View at Publisher · View at Google Scholar
  111. A. W. Stitt, C. He, and H. Vlassara, “Characterization of the advanced glycation end-product receptor complex in human vascular endothelial cells,” Biochemical and Biophysical Research Communications, vol. 256, no. 3, pp. 549–556, 1999. View at Publisher · View at Google Scholar · View at PubMed
  112. A. W. Stitt, Y. M. Li, T. A. Gardiner, R. Bucala, D. B. Archer, and H. Vlassara, “Advanced glycation end products (AGEs) co-localize with AGE receptors in the retinal vasculature of diabetic and of AGE-infused rats ,” The American Journal of Pathology, vol. 150, pp. 523–531, 1997.
  113. A. M. Schmidt, O. Hori, and R. Cao et al., “RAGE: a novel cellular receptor for advanced glycation end products,” Diabetes, vol. 45, supplement 3, pp. S77–S80, 1996.
  114. C. Esposito, H. Gerlach, J. Brett, D. Stern, and H. Vlassara, “Endothelial receptor-mediated binding of glucose-modified albumin is associated with increased monolayer permeability and modulation of cell surface coagulant properties,” Journal of Experimental Medicine, vol. 170, no. 4, pp. 1387–1407, 1989. View at Publisher · View at Google Scholar
  115. S. Yamagishi, H. Yonekura, and Y. Yamamoto et al., “Advanced glycation end products-driven angiogenesis in vitro: induction of the growth and tube formation of human microvascular endothelial cells through autocrine vascular endothelial growth factor,” Journal of Biological Chemistry, vol. 272, no. 13, pp. 8723–8730, 1997. View at Publisher · View at Google Scholar
  116. S. Vasan, P. G. Foiles, and H. W. Founds, “Therapeutic potential of AGE inhibitors and breakers of AGE protein cross-links,” Expert Opinion on Investigational Drugs, vol. 10, no. 11, pp. 1977–1987, 2001. View at Publisher · View at Google Scholar · View at PubMed
  117. X. Xu, Z. Li, and D. Luo et al., “Exogenous advanced glycosylation end products induce diabetes-like vascular dysfunction in normal rats: a factor in diabetic retinopathy,” Graefe's Archive for Clinical and Experimental Ophthalmology, vol. 241, no. 1, pp. 56–62, 2003.
  118. T. A. Kalfa, M. E. Gerritsen, E. C. Carlson, A. J. Binstock, and E. C. Tsilibary, “Altered proliferation of retinal microvascular cells on glycated matrix,” Investigative Ophthalmology & Visual Science, vol. 36, no. 12, pp. 2358–2367, 1995.
  119. T. S. Kern and R. L. Engerman, “Pharmacological inhibition of diabetic retinopathy: aminoguanidine and aspirin,” Diabetes, vol. 50, no. 7, pp. 1636–1642, 2001. View at Publisher · View at Google Scholar
  120. X. Xin, Z. A. Khan, S. Chen, and S. Chakrabarti, “Glucose-induced Akt1 activation mediates fibronectin synthesis in endothelial cells,” Diabetologia, vol. 48, no. 11, pp. 2428–2436, 2005. View at Publisher · View at Google Scholar · View at PubMed
  121. Z. A. Khan, Y. P. Barbin, H. Farhangkhoee, N. Beier, W. Scholz, and S. Chakrabarti, “Glucose-induced serum- and glucocorticoid-regulated kinase activation in oncofetal fibronectin expression,” Biochemical and Biophysical Research Communications, vol. 329, no. 1, pp. 275–280, 2005. View at Publisher · View at Google Scholar · View at PubMed
  122. Y. Nishizuka, “Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C,” Science, vol. 258, no. 5082, pp. 607–614, 1992. View at Publisher · View at Google Scholar
  123. H. Ishii, D. Koya, and G. L. King, “Protein kinase C activation and its role in the development of vascular complications in diabetes mellitus,” Journal of Molecular Medicine, vol. 76, no. 1, pp. 21–31, 1998.
  124. 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. View at Publisher · View at Google Scholar
  125. I. Idris, S. Gray, and R. Donnelly, “Protein kinase C activation: isozyme-specific effects on metabolism and cardiovascular complications in diabetes,” Diabetologia, vol. 44, no. 6, pp. 659–673, 2001. View at Publisher · View at Google Scholar
  126. T. Inoguchi, R. Battan, E. Handler, J. R. Sportsman, W. Heath, and G. L. King, “Preferential elevation of protein kinase C isoform β II and diacylglycerol levels in the aorta and heart of diabetic rats: differential reversibility to glycemic control by islet cell transplantation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 89, pp. 11059–11063, 1992. View at Publisher · View at Google Scholar
  127. T. Shiba, T. Inoguchi, J. R. Sportsman, W. F. Heath, S. Bursell, and G. L. King, “Correlation of diacylglycerol level and protein kinase C activity in rat retina to retinal circulation,” American Journal of Physiology. Endocrinology and Metabolism, vol. 265, no. 5, part 1, pp. E783–E793, 1993.
  128. 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. View at Publisher · View at Google Scholar
  129. Q. Huang and Y. Yuan, “Interaction of PKC and NOS in signal transduction of microvascular hyperpermeability,” American Journal of Physiology. Heart and Circulatory Physiology, vol. 273, no. 5, pp. H2442–H2451, 1997.
  130. F. Pomero, A. Allione, and E. Beltramo et al., “Effects of protein kinase C inhibition and activation on proliferation and apoptosis of bovine retinal pericytes,” Diabetologia, vol. 46, no. 3, pp. 416–419, 2003.
  131. J. Y. Park, N. Takahara, and A. Gabriele et al., “Induction of endothelin-1 expression by glucose an effect of protein kinase C activation,” Diabetes, vol. 49, no. 7, pp. 1239–1248, 2000. View at Publisher · View at Google Scholar
  132. 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.
  133. 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. View at Publisher · View at Google Scholar
  134. 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
  135. R. A. Kowiuru, 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. View at Publisher · View at Google Scholar
  136. R. P. Danis, D. P. Bingaman, M. Jirousek, and Y. Yang, “Inhibition of intraocular neovascularization caused by retinal ischemia in pigs by PKCβ inhibition with LY333531,” Investigative ophthalmology & visual sciencei, vol. 39, no. 1, pp. 171–179, 1998.
  137. M. A. Cotter, A. M. Jack, and N. E. Cameron, “Effects of the protein kinase C β inhibitor LY333531 on neural and vascular function in rats with streptozotocin-induced diabetes,” Clinical Science, vol. 103, no. 3, pp. 311–321, 2002.
  138. The PKC-DRS Study Group, “The effect of ruboxistaurin on visual loss in patients with moderately severe to very severe nonproliferative diabetic retinopathy: initial results of the protein kinase C β inhibitor diabetic retinopathy study (PKC-DRS) multicenter randomized clinical trial,” Diabetes, vol. 54, no. 7, pp. 2188–2197, 2005. View at Publisher · View at Google Scholar
  139. L. P. Aiello, M. D. Davis, and A. Girach et al., “Effect of ruboxistaurin on visual loss in patients with diabetic retinopathy,” Ophthalmology, vol. 113, no. 12, pp. 2221–2230, 2006. View at Publisher · View at Google Scholar · View at PubMed
  140. D. R. Tomlinson, “Mitogen-activated protein kinases as glucose transducers for diabetic complications,” Diabetologia, vol. 42, no. 11, pp. 1271–1281, 1999. View at Publisher · View at Google Scholar
  141. M. Awazu, K. Ishikura, M. Hida, and M. Hoshiya, “Mechanisms of mitogen-activated protein kinase activation in experimental diabetes,” Journal of the American Society of Nephrology, vol. 10, no. 4, pp. 738–745, 1999.
  142. G. Pearson, F. Robinson, and T. B. Gibson et al., “Mitogen-activated protein (MAP) kinase pathways: regulation and physiological,” Endocrine Reviews, vol. 22, no. 2, pp. 153–183, 2001. View at Publisher · View at Google Scholar
  143. H. Fujita, S. Omori, K. Ishikura, M. Hida, and M. Awazu, “ERK and p38 mediate high-glucose-induced hypertrophy and TGF-β expression in renal tubular cells,” American Journal of Physiology. Renal Physiology, vol. 286, pp. F120–F126, 2004. View at Publisher · View at Google Scholar · View at PubMed
  144. M. Toyoda, D. Suzuki, and M. Honma et al., “High expression of PKC-MAPK pathway mRNAs correlates with glomerular lesions in human diabetic nephropathy,” Kidney International, vol. 66, pp. 1107–1114, 2004. View at Publisher · View at Google Scholar · View at PubMed
  145. C. Liebmann, “Regulation of MAP kinase activity by peptide receptor signalling pathway: paradigms of multiplicity,” Cellular Signalling, vol. 13, no. 11, pp. 777–785, 2001. View at Publisher · View at Google Scholar
  146. W. Lui, A. Schoenkerman, and W. L. Lowe Jr., “Activation of members of the mitogen-activated protein kinase family by glucose in endothelial cells,” American Journal of Physiology. Endocrinology and Metabolism, vol. 279, no. 4, pp. E782–E790, 2000.
  147. M. Hayashi, S. W. Kim, and K. Imanaka-Yoshida et al., “Targeted deletion of BMK1/ERK5 in adult mice perturbs vascular integrity and leads to endothelial failure,” Journal of Clinical Investigation, vol. 113, pp. 1138–1148, 2004. View at Publisher · View at Google Scholar
  148. E. N. Olson, “Undermining the endothelium by ablation of MAPK-MEF2 signaling,” Journal of Clinical Investigation, vol. 113, pp. 1110–1112, 2004. View at Publisher · View at Google Scholar
  149. M. P. Scheid and J. R. Woodgett, “PKB/AKT: functional insights from genetic models,” Nature Reviews Molecular Cell Biology, vol. 2, no. 10, pp. 760–768, 2001. View at Publisher · View at Google Scholar · View at PubMed
  150. M. Pap and G. M. Cooper, “Role of glycogen synthase kinase-3 in the phosphatidylinositol 3-kinase/Akt cell survival pathway,” Journal of Biological Chemistry, vol. 273, no. 32, pp. 19929–19932, 1998. View at Publisher · View at Google Scholar
  151. P. A. Baeuerle, “Pro-inflammatory signaling: last pieces in the NF-κB puzzle?,” Current Biology, vol. 8, no. 1, pp. R19–R22, 1998. View at Publisher · View at Google Scholar
  152. P. Quehenberger, A. Bierhaus, and P. Fasching et al., “Endothelin 1 transcription is controlled by nuclear factor-κB in AGE-stimulated cultured endothelial cells,” Diabetes, vol. 49, no. 9, pp. 1561–1570, 2000. View at Publisher · View at Google Scholar
  153. 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. View at Publisher · View at Google Scholar
  154. C. Harada, T. Harada, and Y. Mitamura et al., “Diverse NF-κB expression in epiretinal membranes after human diabetic retinopathy and proliferative vitreoretinopathy,” Molecular Vision, vol. 10, pp. 31–36, 2004.
  155. Y. Mitamura, T. Harada, and C. Harada et al., “NF-κB in epiretinal membranes after human diabetic retinopathy,” Diabetologia, vol. 46, no. 5, pp. 699–703, 2003. View at Publisher · View at Google Scholar · View at PubMed
  156. L. Zheng, S. J. Howell, D. A. Hatala, K. Huang, and T. S. Kern, “Salicylate-based anti-inflammatory drugs inhibit the early lesion of diabetic retinopathy,” Diabetes, vol. 56, no. 2, pp. 337–345, 2007. View at Publisher · View at Google Scholar · View at PubMed
  157. S. Chen, S. Mukherjee, C. Chakraborty, and S. Chakrabarti, “High glucose-induced, endothelin-dependent fibronectin synthesis is mediated via NF-κB and AP-1,” American Journal of Physiology. Cell Physiology, vol. 284, no. 2, pp. C263–C272, 2003.
  158. E. Shaulian and M. Karin, “AP-1 in cell proliferation and survival,” Oncogene, vol. 20, no. 19, pp. 2390–2400, 2001. View at Publisher · View at Google Scholar · View at PubMed
  159. Y. Chinenov and T. K. Kerppola, “Close encounters of many kinds: fos-jun interactions that mediate transcription regulatory specificity,” Oncogene, vol. 20, no. 19, pp. 2438–2452, 2001. View at Publisher · View at Google Scholar · View at PubMed
  160. 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
  161. J. B. Jonas, “Intravitreal triamcinolone acetonide for diabetic retinopathy,” Developments in Ophthalmology, vol. 39, pp. 96–110, 2007.
  162. P. J. Barnes, “Anti-inflammatory actions of glucocorticoids: molecular mechanisms,” Clinical Science, vol. 94, pp. 557–572, 1998.
  163. I. M. Adcock, K. Ito, and P. J. Barnes, “Glucocorticoids: effects on gene transcription,” Proceedings of the American Thoracic Society, vol. 1, pp. 247–254, 2004. View at Publisher · View at Google Scholar · View at PubMed
  164. E. Kalkhoven, “CBP and p300: HATs for different occasions,” Biochemical Pharmacology, vol. 68, no. 6, pp. 1145–1155, 2004. View at Publisher · View at Google Scholar · View at PubMed
  165. R. H. Goodman and S. Smolik, “CBP/p300 in cell growth, transformation, and development,” Genes & Development, vol. 14, no. 13, pp. 1553–1577, 2000.