PROGRESSION OF NEPHROPATHY IN SPONTANEOUS DIABETIC RATS IS PREVENTED BY OPB-9195, A NOVEL INHIBITOR OF ADVANCED GLYCATION

Levels of tissue advanced glycation end products (AGEs) that result fr om nonenzymatic reactions of glucose and proteins are high in both dia betic and aging people. Irreversible AGE formation is based on increas es in AGE-derived protein-to-protein cross-linking and is considered t o be a factor contributing to the complications of diabetes. A novel i nhibitor of advanced glycation, OPB-9195, belongs to a group of thiazo lidine derivatives, known as hypoglycemic drugs; however, they do not lower blood glucose levels. We did studies to determine if OPB-9195 wo uld prevent the progression of nephropathy in spontaneous diabetic rat s. In vitro inhibitory effects of OPN-9195 on AGE formation and AGE-de rived 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-Schif f (PAS) staining, the extent of AGE accumulation detected by immunohis tochemical staining in the kidneys, the levels of serum AGEs by AGE-sp ecific ELISA, and urinary albumin excretion were examined. OPB-9195 ef fectively inhibited both AGE-derived cross-linking and the formation o f AGEs, in a dose-dependent manner in vitro. In addition, the administ ration of OPB-9195 prevented the progression of glomerular sclerosis a nd AGE deposition in glomeruli. Elevation of circulating AGE levels an d urinary albumin excretion were dramatically prevented in rats, even at 56 weeks of age and with persistent hyperglycemia. We concluded tha t a novel thiazolidine derivative, OPB-9195, prevented the progression of diabetic glomerular sclerosis in OLETF rats by lowering serum leve ls of AGEs and attenuating AGE deposition in the glomeruli.