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目的:探讨血管紧张素Ⅱ受体阻滞剂氯沙坦对糖尿病肾损害的保护作用与机制。方法:36只大鼠分成正常对照组、糖尿病模型组和氯沙坦治疗组,每组12只。模型组和氯沙坦组腹腔注射链脲佐菌素65 mg.kg-1建立糖尿病模型,在模型建立1周后氯沙坦组灌胃给予氯沙坦5 mg.kg-1.d-1,共12周。检测各组第1,4,12周血糖、24 h尿视黄醇结合蛋白(RBP)、尿白蛋白(A lb)排泄率;分别于第4和12周每组各处死5只大鼠,取肾,称重,计算肾脏肥大指数;分离肾皮髓质,荧光定量RT-PCR法检测皮质转化生长因子β1(TGFβ1)mRNA水平;透视电子显微镜检查肾小球基底膜、系膜区的病理改变。结果:第4和12周时模型组尿Alb,RBP排泄、肾脏肥大指数和TGFβ1mRNA表达量均显著高于正常对照组(P<0.01),氯沙坦组的这些指标则较模型组明显减少(P<0.01)。电镜显示模型组肾小球毛细血管基底膜增厚,系膜和系膜细胞增生;氯沙坦组肾小球毛细血管基底膜也有不规则增厚,较同时期模型组减轻。结论:氯沙坦对糖尿病肾损害有确切的保护作用,其机制可能部分与氯沙坦抑制肾脏TGFβ1过度表达有关。
Objective: To investigate the protective effect and mechanism of losartan on diabetic nephropathy by angiotensin Ⅱ receptor blocker. Methods: Thirty-six rats were divided into normal control group, diabetic model group and losartan treatment group, with 12 rats in each group. The model group and the losartan group were intraperitoneally injected with streptozotocin (65 mg.kg-1) to establish the model of diabetes mellitus. One week after the model was established, the losartan group was given losartan 5 mg.kg-1.d-1 A total of 12 weeks. The blood glucose, 24 h urinary retinol binding protein (RBP) and urinary albumin (ABI) excretion rate were measured at the 1st, 4th and 12th weeks in each group. Five rats were sacrificed at 4 and 12 weeks, Kidney was weighed, and the renal hypertrophy index was calculated. The renal cortex medulla was separated and the mRNA expression of TGFβ1 was detected by real-time RT-PCR. The pathological changes of glomerular basement membrane and mesangial area were observed by electron microscope change. Results: Urinary Alb, RBP excretion, renal hypertrophy index and TGFβ1 mRNA expression in model group were significantly higher than those in normal control group (P <0.01) at 4 weeks and 12 weeks, and those in losartan group were significantly lower than those in model group P <0.01). Electron microscope showed glomerular capillary basement membrane thickening, mesangial and mesangial cell proliferation; losartan group glomerular capillary basement membrane irregular thickening, compared with the same period the model group reduced. CONCLUSION: Losartan has an exact protective effect on diabetic nephropathy. The mechanism may be related to the inhibition of TGFβ1 overexpression by losartan.