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-LongEvans-Tokushima-Fatty (OLETF) rats, a model of NIDDM, were used to evaluate the therapeutic effect of OPB-9195. Light microscopic findings by periodic acidSchiff (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. Diabetes 46:895-899, 1997

Suppression of transforming growth factor beta and vascular endothelial growth factor in diabetic nephropathy in rats by a novel advanced glycation end product inhibitor, OPB-9195

“…We found OPB-9195 also decreased albumin excretion during the late phase of diabetic nephropathy. In a histological study, OPB-9195 considerably inhibited mesangial expansion, basement thickness, glomerulosclerosis and AGE accumulation in the glomeruli of OLETF rats [29].…”

“…Male Long-Evans-Tokushima-Fatty (LETO) rats served as normal controls. We prepared three groups of four animals each: control group, diabetes group and diabetes with OPB-9195 (Tokushima Research Institute, Otsuka Pharmaceutical) treatment group [29]. In the OPB-9195 treatment group, OPB-9195 was given daily to the OLETF rats from 24 weeks of age by mixing in the chow at a concentration of 1 mg/g.…”

“…They had screened many compounds for candidates as insulin sensitizers and accidentally discovered that OPB-9195 was a strong AGE inhibitor. Using Otsuka-Long-Evans-Tokushima-Fatty (OLETF) rats, we found that OPB-9195 inhibits the formation of AGEs but has no effect in lowering blood glucose, dramatically prevents the development of diabetic nephropathy (as noted microscopically) and significantly prevents sclerotic changes [29]. In addition, albumin excretion by OPB-9195-treated OLETF rats was decreased 60 % compared with untreated OLETF rats [29].…”

Advanced Glycation End Products Increase Collagen-specific Chaperone Protein in Mouse Diabetic Nephropathy

“…An inhibitor of AGEs formation, aminoguanidine, ameliorates the mild glomerular changes and functional changes found in streptozocin-induced diabetic rats (6). Recently, a synthetic thiazolidine derivative, OPB-9195, was shown to have a strong inhibitory effect of AGE formation (7).…”

Medical treatment of diabetic retinopathy

“…These compounds, which share a common thiazolium structure, have the ability to reduce tissue content of AGEs in experimental diabetes, 80 ameliorate age-related myocardial stiffness, 81 and reverse hyperglycaemia-related arterial distensibility. 73,82 Oxidation Free radicals are unstable chemical derivatives of oxygen that carry unpaired electrons and are the by-products of metabolism, especially mitochondrial oxidative phosphorylation. Increased oxidative stress, giving rise to free radical-mediated damage to proteins, nucleic acid, and lipids, is a plausible mechanism of injury in many disease states including diabetes.…”