罗格列酮对高脂饲料喂养肥胖大鼠肾脏保护作用及其机制探讨

The Protective Effects of Rosiglitazone on Kidney in Diet-induced Obese Rats

目的观察罗格列酮对高脂饲料喂养的肥胖大鼠肾脏是否具有保护作用并探讨其机制。方法雄性Wistar大鼠随机分为对照组、肥胖组、罗格列酮组,每组8只。分别予以普通饲料喂养4周后以生理盐水灌胃、高脂饲料喂养4周后以生理盐水灌胃或4mg/(kg·d)罗格列酮灌胃。总共喂养24周后,称重,测量血液中的生化指标,留取尿液测定尿白蛋白/肌酐比值(ACR),测定主动脉血管舒张功能。观察肾脏形态学及肾小球CD31表达,测定肾小球一氧化氮(NO)水平,Western blot检测肾小球血管内皮生长因子(VEGF)蛋白水平。结果肥胖组大鼠体质量、内脏脂肪质量、血游离脂肪酸(FFA)与甘油三酯(TG)水平较正常组增加(P<0.05);与肥胖组比较,罗格列酮组大鼠体质量无明显变化,内脏脂肪质量、血FFA与TG下降(P<0.01),但仍高于正常组(P<0.05)。肥胖组大鼠ACR水平较正常组增加(P<0.01),罗格列酮组大鼠ACR较肥胖组降低(P<0.01),但仍高于正常组(P<0.05)。肥胖组大鼠内皮依赖性舒张功能(EDV)较正常组受损(P<0.05),罗格列酮组大鼠EDV较肥胖组大鼠改善(P<0.05),接近正常大鼠水平(P>0.05)。与正常组比较,肥胖组大鼠肾小球体积增大(P<0.01),CD31表达增多(P<0.05);罗格列酮组大鼠较肥胖组大鼠肾小球体积减小(P<0.01),CD31表达减少(P<0.05),接近正常大鼠水平(P>0.05)。与正常组比较,肥胖组大鼠肾小球VEGF水平增高(P<0.05),肾小球NO水平下降(P<0.05)。罗格列酮组大鼠较肥胖组大鼠肾小球VEGF水平降低(P<0.05),但仍高于正常组(P<0.05),肾小球NO水平增加(P<0.05),但仍低于正常组(P<0.05)。结论罗格列酮降低肥胖大鼠尿白蛋白排出量减轻肾小球肥大,对肥胖大鼠肾脏有保护作用。其机制可能与改善脂质代谢,纠正肾小球VEGF-NO轴失衡及改善血管内皮细胞功能有关。

Objective To investigate whether rosiglitazone has renal protective effects in diet-induced obese rats. Methods Wistar rats were randomly divided into normal control （NC）,obesity （OB） and rosiglitazone （OB＋ R） group （n =8 in each group）. The NC group was fed with normal diet. The OB and OB＋R groups were fed with high-fat diet. Four weeks later, rosiglitazone〔4 mg/（kg· d）〕was given to the OB＋R group by oral gavage. The other two groups were given the same amount of physiological saline in the same manner. After 24 weeks,urinary albumin/creatinine ratio （ACR） was measured. Endothelial function was determined by measuring vasodilatation of aorta. Renal tissues were collected for morphological and CD31 immunohistochemistry. Glomerular vascular endothelial growth factor （VEGF） and nitric oxide （NO） levels were measured. Results Body weight, visceral fat, plasma free fatty acids （FFAs）,plasma triglyceride and ACR levels increased significantly in the obese rats （P〈0.01）. Rosiglitazone intervention decreased visceral fat, plasma FFAs, plasma triglyceride and ACR levels （P〈0.01）,which were still higher than NC group （P〈0. 01）. ACR levels of the OB group were higher than those of NC group （F〈0. 01）,while those of OB＋R group were lower than those in OB group （P〈0. 01）,but still higher than those of NC group （P 〈C 0. 05）. Endothelium-dependent vasodilatation was impaired in the obese rats. Rosiglitazone intervention could enhance acetylcholine-induced vasorelaxation and improved endothelium-dependent vasodilatation （P 〈0. 05）,which was similar to that in NC group （P〉0.05）.Morphological and immunohistochemistry results showed glomerulomegalia, increased glomerular CD31 expression and increased proliferation of glomerular endothelial celLs, which were improved by rosiglitazone （P〈0.05）. Obese rats showed increased glomerular VEGF and reduced NO levels （P〈0. 05）. This imbalance of VEGF/NO was partly improved by rosiglitazone intervention （P〈0.05）. Conclusion Rosiglitazone reduces urinary albumin excretion and has renal protective effects by improving the imbalance of VEGF/NO and endothelial dysfunction in diet-induced obese rats.