Progression of nephropathy in spontaneous diabetic rats is prevented by OPB-9195, a novel inhibitor of advanced glycation
Progression of nephropathy in spontaneous diabetic rats is prevented by OPB-9195, a novel inhibitor of advanced glycation
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DOI：
10.2337/diabetes.46.5.895
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发表时间：
1997-05-01
期刊：
影响因子：
7.7
通讯作者：
Koike, T
中科院分区：
文献类型：
--
作者：
Nakamura, S;Makita, Z;Koike, T
由葡萄糖和蛋白质的非酶反应产生的组织晚期糖基化终末产物(AGEs)水平在糖尿病和老年人中都很高。不可逆的AGE形成是基于AGE衍生的蛋白质对蛋白质交联度的增加，被认为是导致糖尿病并发症的一个因素。一种新的晚期糖基化抑制剂OPB-9195属于一组被称为降血糖药物的噻唑烷衍生物；然而，它们不能降低血糖水平。我们进行了研究，以确定OPB-9195是否可以防止自发性糖尿病大鼠肾病的进展。采用酶联免疫吸附试验(ELISA)和SDS-PAGE检测OPN-9195对AGE形成和AGE衍生的交联物的体外抑制作用。采用NIDDM大鼠OLETF模型，评价OPB-9195的治疗作用。光镜观察高碘酸席夫(PAS)染色，免疫组织化学染色检测肾脏AGE蓄积程度，AGE特异性酶联免疫吸附试验(EL ISA)检测血清AGEs水平，尿白蛋白排泄量。OPB-9195在体外以剂量依赖的方式有效地抑制AGE诱导的交联和AGEs的形成。此外，OPB-9195的应用阻止了肾小球硬化的进展和肾小球中的AGE沉积。循环AGE水平的升高和尿白蛋白排泄在大鼠中得到显著防止，即使在56周龄和持续性高血糖的情况下也是如此。我们的结论是，一种新型的噻唑烷衍生物OPB-9195可以通过降低血清AGEs水平和减少AGE在肾小球中的沉积来预防OLETF大鼠糖尿病肾小球硬化的进展。
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 OPN-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.