【摘要】 目的 本研究观察高脂饮食对阿霉素肾病（ADR）模型大鼠肾脏TGF-β1基因表达的影响，并探讨辛伐他汀及苯那普利对ADR大鼠肾脏TGF-β1基因表达的影响。
方法 根据大鼠TGF-β1cDNA的序列，设计TGF-β1逆转录聚合酶链反应(RT-PCR)的引物，以RT-PCR法观察不同组大鼠肾脏TGF-β1mRNA在4，8，12周时的表达，并以GAPDH为内参照；标记(地高辛)TGF-β1探针，在不同组大鼠的肾
组织冰冻切片上作原位杂交，检测12周时大鼠肾脏TGF-β1mRNA的表达情况。
结果 高脂饮食ADR大鼠4，8，12周时肾脏TGF-β1mRNA表达逐步上调，8，12周明显高于普通饲料肾病大鼠，12周时原位杂交结果表明高脂饮食肾病组肾脏TGF-β1mRNA增强明显，以小管间质为主，而普通饲料肾病组TGF-β1mRNA表达主要在小管间质，呈局灶性分布； 辛伐他汀组和苯那普利组大鼠肾脏TGF-β1mRNA表达较高脂饮食肾病大鼠组明显降低；正常大鼠高脂饮食组 TGF-β1mRNA表达在12周时高于正常对照组。
结论 高脂饮食ADR大鼠肾脏促纤维化因子TGF-β1mRNA随时间延长表达明显上调，表达以小管间质为主；辛伐他汀及苯那普利能明显降低肾脏TGF-β1mRNA的表达，辛伐他汀降低肾脏TGF-β1mRNA的作用机制可能与降低高脂血症相关的RAS活性有关，还可能与抑制MVA通路的间接作用有关；而苯那普利降低大鼠肾脏TGF-β1mRNA表达与其直接抑制AngⅡ介导作用有关。
【关键词】 高脂血症；纤维化；TGF-β1；辛伐他汀；苯那普利
【Abstracts】 Objective This study was to examine the changes of renal TGF-β1 mRNA expression in ADR experimental nephropathy rats given high lipid diet and the effect of using simvastatin and benazepril.
Methods Using RT-PCR to detect the expression of renal TGF-β1 mRNA in different groups at 4，8 and 12 weekend， the GAPDH mRNA expression used as control. Using in situ hybridization to examine TGF-β1 gene expression in different groups at 12 weekend.
Results TGF-β1 mRNA expression of ADR nephrotic rats increased steadily after 4 weekend and its gene expression was higher than that with normal diet at 8 and 12 weekend. The results of using in situ hibrydization showed high level of TGF-β1 mRNA positive signal at 12 weekend in ADR nephrotic rats given high lipid diet，the positive signals mainly located in tubulointerstitial zone disseminately while few found in glomerular， and focal gene positive signals distributed in tubulointerstitial was showed in normal dietary nephrotic rats.The expression of TGF-β1 mRNA decreased in Simvastatin and Benazepril groups significantly.There was no different expression of TGF-β1 mRNA between normal rats given high lipid diet and normal diet during 4 and 8weekend but slight higher gene expression came in high lipid dietary group at 12 weekend compared with normal control.
Conclusion The expression of TGF-β1 mRNA in ADR nephrotic rats given high lipid diet increased steadily as time went on，the positve signals of TGF-β1 mRNA mainly located in tubulointerstitial zone. The treatment of simvastatinor benazepril were proved to be effective in decreasing the high expression of TGF-β1 mRNA in ADR nephrotic rats given high lipid diet. The possible effect of simvastatin is due to reducing the activity of RAS induced by hyperlipidemia or through its negative effect on MVA pathway； while benazepril’s inhibition on this gene expression might be mediated by inhibiting the production of angiotensin Ⅱ.
【Key words】 hyperlipidemia；fibrosis；TGF-β1；simvastatin；benazepril
动物模型中，高脂饮食在一定的观察期后能形成类似人FSGS病变。肾病大鼠给予高脂饮食后，肾小球硬化明显加重，并加速进展至CRF［1］。近年来，大量的研究显示多种细胞因子参与肾病进程，其中起主要作用的是TGF-β1［2］。TGF-β1广泛分布于血小板，巨噬细胞及肾脏组织，能通过增加ECM蛋白的合成，抑制其降解及调节细胞-整合素受体促进ECM的积聚， 并吸引单核细胞和刺激成纤维细胞转变成纤维细胞，促进肾脏硬化［3］。目前认为，TGF-β1在肾组织中持续过度表达是引起肾小球硬化的重要原因［4］。我们用RT-PCR和原位杂交观察
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