Abstract
Purpose: To examine the effects of poly(ADP-ribose)polymerase-1 (PARP-1) inhibitor 1,5-isoquinolinediol (IQ) on nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-derived oxidative stress in diabetic retina. Methods: Streptozotocin-induced diabetic rats were treated with IQ. The NADPH oxidase enzyme activity was determined by luminometer. Expression of gp(91phox), P-47phox and nitrated proteins was examined by western blot. Interaction between gp(91phox) and P-47phox was determined by coimmunoprecipitation. Enzyme-linked immunosorbent assay was utilized to measure the level of retinal total antioxidant capacity. We also studied the effect of the IQ on hydrogen peroxide (H2O2)-induced cleavage of PARP-1 and caspase-3 in human retinal Muller glial cells. Results: Treatment of retinal Muller cells with H2O2-induced PARP-1 and caspase-3 cleavage that was attenuated by IQ cotreatment. Diabetes upregulated PARP-1, NADPH oxidase enzyme activity, gp(91phox), P-47phox, nitrated protein expression and interaction between gp(91phox) and P-47phox, and downregulated total antioxidant capacity in the retinas compared with nondiabetic rats. Administration of IQ did not affect the metabolic status of the diabetic rats, but it significantly attenuated diabetes-induced upregulation of NADPH oxidase enzyme activity and expressions of gp(91phox), P-47phox, and nitrated proteins and interaction between gp(91phox) and P-47phox. In addition, IQ ameliorated diabetes-induced downregulation of total antioxidant capacity in the retina. Conclusion: PARP-1 inhibition by IQ protects diabetic retina from NADPH oxidase-derived oxidative stress. Thus, inhibition of PARP-1 could have potential therapeutic value in preventing the development of diabetic retinopathy.