大麻素受体1拮抗剂ZH-101-S对糖尿病大鼠肾脏的保护作用

目的: 探讨新型大麻素受体1拮抗剂ZH-101-S对糖尿病大鼠肾脏的作用及机制。方法: 通过腹腔注射链脲佐菌素建立糖尿病大鼠模型，随机分为糖尿病组和低、中、高剂量组，每组6只，低、中、高剂量组分别于每天腹腔注射0.3，1.0，3.0 mg/kg ZH-101-S，另以健康大鼠作为对照组，对照组和糖尿病组腹腔注射等量生理盐水，8周后检测各组大鼠血尿素氮、血肌酐和尿白蛋白排泄率(urine albumin excretion rate, UAER)，测定肾组织丙二醛含量和超氧化物歧化酶(SOD)活力，HE染色观察肾组织病理改变，免疫印迹法检测肾组织细胞电压依赖性离子通道(voltage-dependent anion channel, VDAC)蛋白的表达。结果： 与对照组比较，糖尿病组大鼠血肌酐、血尿素氮和UAER明显增高；肾组织SOD活性降低，丙二醛含量升高(P<0.05)；肾组织细胞VDAC表达明显降低(P<0.01)；肾小球体积增大，肾小管上皮细胞水肿，系膜基质增多。与糖尿病组比较，高剂量组大鼠UAER、血肌酐和血尿素氮明显降低；肾组织SOD活性明显升高，丙二醛含量明显降低；肾脏细胞VDAC表达增加(P<0.05)；肾组织病理形态得到一定改善。结论： ZH-101-S对糖尿病肾病大鼠肾脏具有保护作用，可能与抑制氧化应激和改善肾脏线粒体功能有关。

Protective effect of novel CB1 receptor antagonist ZH-101-S on renal function in diabetic rats

Objective To investigate the protective effect of novel cannabinoid(CB) 1 receptor antagonist ZH-101-S on kidneys in streptozotocin induced diabetic rats. MethodsDiabetic models were established by intraperitoneal injection of streptozotocin, rats were randomized into diabetes mellitus group(DM group, normal saline, i.p.), low dose group(0.3 mg/kg ZH-101-S, i.p.), middle dose group(1.0 mg/kg ZH-101-S, i.p.), and high dose group(3.0 mg/kg ZH 101 S, i.p.); and healthy rats were selected as control group(normal saline, i.p.). After 8 weeks, the serum urea nitrogen(BUN), serum creatinine(Scr), urine albumin excretion rate(UAER), and the level of malondialdehyde(MDA) and the activity of superoxide dismutase(SOD) in renal tissues were detected; the pathological changes of renal tissues were observed by HE staining; the expression of voltage-dependent anion channel(VDAC) protein in renal tissues were examined by Western blotting. ResultsCompared with control group, DM group showed higher levels of UAER, Scr and BUN(P<0.05), decreased SOD activity(P<0.01), and increased expression of MDA(P<0.05); decreased VDAC expression(P<0.01); glomerular volume increased, renal tubular epithelial cell edema, mesangial matrix increased. Compared with DM group, high dose group had lower levels of UAER, Scr and BUN, increased SOD activity, lower content of malondialdehyde; increased VDAC expression(P<0.01), the pathological morphology of the kidney was improved. ConclusionZH-101-S showed protective effect on the kidney of diabetic rats, which may be related to the inhibition of oxidative stress and the improvement of kidney mitochondrial function.