斯伐他汀对大鼠实验性肾间质纤维化的影响及其机制探讨

Effect of simvastatin on experimental interstitial fibrosis and its mechanism

目的 研究羟甲基戊二酰辅酶Ａ（ＨＭＧ－ＣｏＡ）还原酶抑制剂斯伐他汀（ｓｉｍｖａｓｔａｔｉｎ）对大鼠肾间质成纤维细胞（ＲＦＢ）和５／６肾切除动物模型的影响及其可能机制。方法 通过原代大鼠肾间质成纤维细胞培养和建立大鼠５／６肾切除慢性肾功能衰竭模型，应用甲基噻唑基四唑（ＭＴＴ）比色法、放射性免疫组织化学，半定量逆转录－聚合酶链反应（ＲＴ－ＰＣＲ）等技术，观察ｓｉｍｖａｓｔａｈｎ对动物模型的防治作用及对ＲＦＢ的影响。结果ｓｉｍｖａｓｔａｔｉｎ治疗组大鼠血脂、血肌酐、尿酸及体重明显下降，与模型对照组比较差异有显著性意义（Ｐ＜０．０５＝，血尿素氮变化不明显。治疗１２周后，光镜观治疗组大鼠肾间质纤维化的程度降低。ｓｉｍｖａｓｔａｔｉｎ可抑制ＲＦＢ的增殖活性（Ａ值），减少ＲＦＢ层粘连蛋白（ＬＮ）的合成，使ｃ－ｆｏｓ ｍＲＮＡ的表达逐渐下降，呈一定的剂量依赖性，各浓度加药组与正常对照组比较差异有显著性意义（Ｐ＜０．０５）。结论 ｓｉｍｖａｓｔａｔｉｎ可通过抑制细胞增殖，减少细胞外基质的合成以及阻断与细胞增殖有关的ｃ－ｆｏｓ依赖性有丝分裂途径等机制对实验性肾间质纤维化有一定的防治作用。

Objective To evaluate the effect and mechanism of HMG-CoA reductase inhibitor simvastatin on experimental interstitial fibrosis. Methods Experiments on rat 5/6 nephrectomy chronic renal failure model and primary cultured renal interstitial fibroblast cells were conducted in this study. The cell proliferation, extracellular matrix, c-fos mRNA expression of rat interstitial fibroblasts were measured by MTT assay, immunohistochernitry, semi-quantitative reverse-transcript PCR methods, respectively. Results Serum cholesterol, triglyceride and creatinine of treated group were significantly reduced by simvastatin as compared with controls. No statistical significance in BUN was observed between untreated and simvastatin-treated rats. Histological examination revealed that simvastatin caused a reduction in the glomeruli with sclerosis. Tubulointerstitial injury paralleled the degree of glomerular damage. Simvastatin in a dose-dependent manner inhibited the proliferation of renal intersititial fibroblasts, decreased the secretion of lamimn( LN), and suppressed the expression of c-fos mRNA, as compared with normal controls. No obvious effect on hyaluronic acid( HA) secretion of fibroblasts was found. Conclusions Simvastatin is anti-proliferative in interstitial fibroblasts and decreases the secretion of laminin. This effect is exerted, at least in part, via inhibition of the c-fos and c-jun-dependent mitogenic pathway. Simvastatin may prevent interstitial fibrosis development and attenuate renal damage in uremic rats with hvperlipidemia.