Progression of Nephropathy in Spontaneous Diabetic Rats Is Prevented by OPB-9195, a Novel Inhibitor of Advanced Glycation

Abstract

Levels of tissue advanced glycation end products (AGEs) that result from nonenzymatic reactions of glucose and proteins are high in both diabetic and aging people. Irreversible AGE formation is based on increases in AGE-derived protein-to-protein cross-linking and is considered to be a factor contributing to the complications of diabetes. A novel inhibitor of advanced glycation, OPB-9195, belongs to a group of thiazolidine derivatives, known as hypoglycemic drugs; however, they do not lower blood glucose levels. We did studies to determine if OPB-9195 would prevent the progression of nephropathy in spontaneous diabetic rats. In vitro inhibitory effects of OPB-9195 on AGE formation and AGE-derived cross-linking were examined by enzyme-linked immunosorbent assay (ELISA) and SDS-PAGE, respectively. Otsuka-Long-Evans-Tokushima-Fatty (OLETF) rats, a model of NIDDM, were used to evaluate the therapeutic effect of OPB-9195. Light microscopic findings by periodic acid-Schiff (PAS) staining, the extent of AGE accumulation detected by immunohistochemical staining in the kidneys, the levels of serum AGEs by AGE-specific ELISA, and urinary albumin excretion were examined. OPB-9195 effectively inhibited both AGE-derived cross-linking and the formation of AGEs, in a dose-dependent manner in vitro. In addition, the administration of OPB-9195 prevented the progression of glomerular sclerosis and AGE deposition in glomeruli. Elevation of circulating AGE levels and urinary albumin excretion were dramatically prevented in rats, even at 56 weeks of age and with persistent hyperglycemia. We concluded that a novel thiazolidine derivative, OPB-9195, prevented the progression of diabetic glomerular sclerosis in OLETF rats by lowering serum levels of AGEs and attenuating AGE deposition in the glomeruli.