The role of poly(ADP-ribose) polymerase-1 and NF-kappaB in the development of diabetic retinopathy

Diabetic retinopathy is the leading cause of acquired blindness in adults in the United States. Degeneration of retinal capillaries plays a critical role in the eventual development of impaired visions in diabetes. New and more effective pharmacologic agents are in great need to prevent diabetic retinopathy. The goals of this thesis project were to (1) investigate the pathogenesis of diabetic retinopathy using animal models, and (2) identify therapeutic targets at which the retinopathy might be inhibited. The present study demonstrated increased PARP-1 activity (Chapter 2) and NF-kappaB activation (Chapter 3) in whole retina and in retinal endothelial cells of diabetic rats. In Chapter 2, administration of a potent inhibitor of PARP-1 (PJ-34) to diabetic rats for nine months significantly inhibited the diabetes-induced death of retinal microvascular cells and the development of degenerate (acellular) capillaries. PJ-34 also inhibited diabetes-induced increase in leukocytes adhering to the retinal vessels, which has been postulated to contribute to vessel occlusion in retina of diabetic animals. In chapter 3, administration of aspirin, sodium salicylate and sulfasalazine, which are known to inhibit NF-kappaB activation, significantly inhibited the formation of the degenerate (acellular) capillaries. Sulfasalazine also inhibited diabetes-induced retinal dysfunction demonstrated by the amplitudes of a- and b-waves of the electoretinogram. The beneficial effects of these salicylate-based drugs on diabetic retinopathy likely are via anti-inflammatory effects mediated by inhibition of NF-kappaB. Sulfasalazine inhibited diabetes-induced up-regulation of ICAM-1, VCAM, iNOS, and COX-2 expression in the retinas, and all of these genes are regulated by NF-kappaB. In chapter 4, the results demonstrated that PARP-1 interacted directly with both subunits of NF-kappaB (p50 and p65) in bovine retinal endothelial cells (BRECs) and rat retinal Muller cells incubated in a diabetic-like concentration of glucose. PJ-34 blocked the hyperglycemia-induced increase in NF-kappaB activation in BRECs, and the diabetes-induced overexpression of ICAM-1 and iNOS in retinas of diabetic rats. In conclusion, PARP-1 regulates NF-kappaB activation, and both are involved in the development of diabetic retinopathy. Inhibitors of PARP-1 or NF-kappaB might have clinical efficacy in inhibiting the development of diabetic retinopathy.