糖尿病大鼠肾组织中PPAR-γ对TGF-β1、c-Ski调控作用的研究

The regulation of PPAR-γ on TGF-β1 and c-Ski in kidney tissue of diabetic rats

目的:观察转化生长因子TGF-β1和核转录共抑制因子c-Ski在糖尿病(DM)大鼠肾组织中的表达,初步探讨过氧化物酶体增殖物激活受体γ(PPAR-γ)对TGF-β1及TGF-β/Smad信号途径的阻遏子c-Ski的调控作用与糖尿病肾病(DN)的关系。方法:建立链脲佐菌素(STZ,40 mg/kg)诱导的糖尿病大鼠模型,随机分为正常对照组(NC)、DM组和药物干预组[吡格列酮15 mg/(kg.d),PT]。每周测量体质量,每2周测定血糖。实验8周后处死各组大鼠,死前1 d代谢笼收集24 h尿液检测24 h尿蛋白定量(UMA),取血检测血尿素氮(BUN)、甘油三酯(TG),HE染色观察肾组织的病理形态,免疫组化法检测肾小球中TGF-β1和c-Ski的蛋白表达情况,并进行半定量分析。结果:与正常组相比,模型组24 h尿量、24 h UMA、BUN、TG、左肾/体质量比(LKW/BWT)和TGF-β1表达量显著增加(P<0.01),而c-Ski表达量显著降低(P<0.01);施加吡格列酮干预后,相关生化指标和TGF-β1显著降低(P<0.05),而c-Ski表达量显著升高(P<0.01)。结论:DM大鼠肾组织中,PPAR-γ激动剂吡格列酮可能通过上调c-Ski的表达抑制TGF-β1的表达,对于延缓DN进程具有重要意义。

Objective： To investigate the regulation of PPAR-γ on TGF-β1 and c-Ski, the repressor of TGF-β/Smad pathway, and the relationship with diabetic nephropathy. Methods： All the SD rats were randomized into normal control group （NC）, diabetes group （DM） and treatment group （PT）. The diabetic models were induced with streptozotocin （STZ）. The body mass weight was measured every week, and the level of blood glucose was measured every two weeks. All the indicators related to renal function such as blood urea nitrogen （BUN）, Triglyceride （TG）, 24 h urinary microalbumin （UMA） and kidney hypertrophy index （LKW/BWT） were detected in rats sacrificed after 8 weeks of experiment. The 24 hour urine of all the rats were collected one day before they died. All the nephridial tissues underwent hematoxylin and eosin stain to observe pathological morphology of nephridial tissues. The protein expressions of TGF-β1 and c-Ski were determined by immunohistochemistry. Results： Compared with NC group, the levels of 24 h urinary volume, 24 h UMA, BUN, TG, LKW/ BWT and TGF-β1 were significantly higher （P〈0.01） while c-Ski was significantly lower in the DM group（P〈0.01）. After treatment with pioglitazone, all the related biochemical data and TGF-β1 decreased significantly （P〈0.05）, while c-Ski was higher （P〈0.01）. Conclusion： Pioglitazone could significantly up-regulate protein level of c-Ski and inhibit TGF-β1 in kidney tissue of diabetic rats, which may play an important role in ameliorating the process of diabetic nephropathy.