大黄酸和辛伐他汀对db/db糖尿病小鼠脂代谢紊乱和肾脏保护作用的比较

Comparative effects of rhein and simvastatin on dyslipidemia and diabetic nephropathy in db/db mouse

目的比较大黄酸和辛伐他汀对糖尿病db/db小鼠脂代谢紊乱的影响以及它们对糖尿病肾病肾脏损伤的保护作用。方法8周龄的db/db和db/m小鼠分为四组Adb/m正常对照组;Bdb/db糖尿病对照组;Cdb/db糖尿病大黄酸[150mg/(kg.d)]治疗组;Ddb/db糖尿病辛伐他汀[20mg/(kg.d)]治疗组;于不同治疗时间测定各组体重、血糖、血脂(胆固醇、三酰甘油、高密度脂蛋白、低密度脂蛋白、载脂蛋白E)、血肌酐、24h尿白蛋白水平。肾组织病理切片行HE、PAS染色,采用图像分析软件对肾小球病理形态学改变进行半定量分析。免疫组化观察肾组织转化生长因子(transforminggrowthfactor-β,TGF-β)以及纤维粘连蛋白(fibronectin,FN)的表达。结果治疗12周时大黄酸治疗组血糖较糖尿病对照组下降、体重减轻,治疗8周时大黄酸和辛伐他汀治疗组血胆固醇、三酰甘油、低密度脂蛋白以及载脂蛋白E较糖尿病对照组均明显下降,二组疗效无明显差异。治疗8周时大黄酸组24h尿白蛋白排泄较糖尿病对照组均有明显下降(P<0.05),而辛伐他汀组在治疗12周时尿白蛋白排泄方有所下降。治疗12周时大黄酸组肾脏肥大、基质增生明显改善,辛伐他汀组肾组织病理也有所改善,但大黄酸治疗组效果更加明显。大黄酸组肾组织TGF-β、FN表达较糖尿病对照组有明显下降(P<0.05),辛伐他汀治疗组TGF-β、FN表达较糖尿病对照组有所下降但无显著性差异(P>0.05)。结论大黄酸治疗后明显降低db/db小鼠血糖,减轻体重,而辛伐他汀对于血糖和体重无明显影响;大黄酸和辛伐他汀均能够改善2型糖尿病模型db/db小鼠的脂代谢紊乱,二者疗效无明显差异;大黄酸降低尿白蛋白排泄量以及稳定肾功能的作用比辛伐他汀更加明显;大黄酸减少肾小球肥大以及细胞外基质增生的作用比辛伐他汀更为显著;大黄酸对TGF-β、FN表达的下调作用也明显强于辛伐他汀;大黄酸是一种不同于辛伐他汀的新的降低血脂、治疗糖尿病肾病的药物。

Objective：To compare the regulating and protecting effects of rhein and simvastatin on dyslipidemia and renal injury in diabetic nephropathy. Methodology：Twenty-four db/db and db/m mouse with 8 weeks of age were divided into five groups according to their treatment ways： group A db/m was treated with saline; group B db/db with saline; group C db/db with rhein [ 150 mg/（ kg· d）], and group D db/db was treated with simvastatin [ 20 mg/（ kg· d ）]. The body weight, plasma glucose, lipids level, 24h urinary albumin excretion were measured every 4 weeks. The morphometry and immunohistology of transforming growth factor-β1 （TGF-β1 ） and fibronectin （FN） were performed in all groups at the end of the study. Results ：The plasma levels of cholesterol, triglyceride, low density lipoprotein and ApoE were all decreased in groups C and D than that in group B after treatment of 8 weeks. Urinary albumin excretion were reduced after treatment of 8 weeks in groups C and 12 weeks in groups D compared with group B （ P 〈 0. 05 ）. The morphometric analysis revealed that the glomerular tuff area （GTA） and extracellular matrix area （ECMA） were significantly decreased in groups C but not in group D compared with that in diabetic control group at age of 20 weeks. In immunohistochemistry, TGF-β and FN expression of renal tissue was markedly decreased in groups C compared with that in group B at 20 weeks （ P 〈 0. 05 ）, but they were not significantly decreased in group D （ P 〉 0. 05 ）. Conclusion： Our data suggested that rhein has a similar effect to simvastatin on regulating dyslipidemia in diabetic db/db mouse. However, rhein also presents a more effective renal protection than simvastatin in diabetic nephropathy.