Aldose Reductase Inhibition Counteracts Oxidative-Nitrosative Stress and Poly(ADP-Ribose) Polymerase Activation in Tissue Sites for Diabetes Complications

Aldose Reductase Inhibition Counteracts Oxidative-Nitrosative Stress and Poly(ADP-Ribose) Polymerase Activation in Tissue Sites for Diabetes Complications Irina G. Obrosova 1 2 , Pal Pacher 3 , Csaba Szabó 4 , Zsuzsanna Zsengeller 4 , Hiroko Hirooka 5 , Martin J. Stevens 1 and Mark A. Yorek 6 1 Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 2 Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana 3 Laboratory of Physiological Studies, National Institutes of Health/National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland 4 Inotek Pharmaceuticals, Beverly, Massachusetts 5 Drug Development Research Laboratories, Sanwa Kagaku Kenkyusho, Mie, Japan 6 Veterans Affairs Medical Center and Department of Internal Medicine, University of Iowa, Iowa City, Iowa Address correspondencereprint requests to Irina G. Obrosova, PhD, Pennington Biomedical Research Center, Louisiana State University, 6400 Perkins Rd., Baton Rouge, LA 70808. E-mail: obrosoig{at}pbrc.edu Abstract This study evaluated the effects of aldose reductase inhibition on diabetes-induced oxidative-nitrosative stress and poly(ADP-ribose) polymerase (PARP) activation. In animal experiments, control and streptozotocin-induced diabetic rats were treated with or without the aldose reductase inhibitor (ARI) fidarestat (16 mg · kg −1 · day −1 ) for 6 weeks starting from induction of diabetes. Sorbitol pathway intermediate, but not glucose, accumulation in sciatic nerve and retina was completely prevented in diabetic rats treated with fidarestat. Sciatic motor nerve conduction velocity, hindlimb digital sensory nerve conduction velocity, and sciatic nerve concentrations of two major nonenzymatic antioxidants, glutathione and ascorbate, were reduced in diabetic versus control rats, and these changes were prevented in diabetic rats treated with fidarestat. Fidarestat prevented the diabetes-induced increase in nitrotyrosine (a marker of peroxynitrite-induced injury) and poly(ADP-ribose) immunoreactivities in sciatic nerve and retina. Fidarestat counteracted increased superoxide formation in aorta and epineurial vessels and in in vitro studies using hyperglycemia-exposed endothelial cells, and the DCF test/flow cytometry confirmed the endothelial origin of this phenomenon. Fidarestat did not cause direct inhibition of PARP activity in a cell-free system containing PARP and NAD + but did counteract high-glucose–induced PARP activatio