环孢菌素A致大鼠肾小管间质细胞凋亡及Losartan、Enalapril的保护作用

APOPTOSIS INDUCED BY CYCLOSPORINE A IN RENAL TUBULAR AND INTERSTITIAL CELLS AND THE PROTECTIVE EFFECTS OF ENALAPRIL AND LOSARTAN ON IT

以低盐饮食 (钠含量 0 .0 5 % )饲养大鼠 7天后随机分成①对照组 ,②CsA处理组 ,③CsA +盐酸维拉帕米处理组 ,④CsA +Losartan处理组 ,⑤CsA +Enalapril处理组。CsA皮下注射剂量为 15mg/ (kg·d) ,连续 4周。用TUNEL法检测凋亡细胞 ,免疫组化方法观察增殖细胞核抗原 (PCNA)、Fas抗原表达。结果发现CsA处理后大鼠肾小管间质凋亡细胞较对照组明显增加 ,增殖细胞也有代偿性增加 ,肾小管上皮细胞Fas抗原表达增多。与CsA处理组相比 ,Losartan、Enalapril处理组肾小管间质细胞凋亡和Fas抗原表达明显减少。结果提示CsA可促进肾小管间质细胞凋亡 ,导致肾小管间质纤维化 ,Fas可能是介导肾小管细胞凋亡的重要介质。Losartan、Enalapril对CsA所致的肾小管间质细胞凋亡有保护作用。

The rats were fed on low salt diet for seven days,and then were randomly divided into five groups: control (n=7), CsA treated (n=7), CsA+Verapamil (n=7), CsA+Enalapril (n=7) and CsA+Losartan (n=7).CsA was given by subcutaneous injection (15mg·kg -1·d -1) for four weeks. The apoptosis of tubular and interstitial cells was detected by TUNEL assay. The proliferating cell nuclear antigen and Fas antigen expression were examined by immunohistochemical staining. Apoptosis of tubular and interstitial cells increased in CsA treated rats. CsA+Losartan and CsA+Enalapril treated rats had a statistically significant decrease in apoptosis when compared to CsA treated rats (7.3±1.1 and 6.6±0.8 vs 13.9±1.2 respectively, P<0.01 in all),and the tubular Fas antigen expression in CsA + Losartan or CsA+ Enalapril group was significantly lower than in CsA treated group(19.8±2.4 and 18.2±1.8 vs 37.8±5.7 respectively, P<0.01 in all).The results showed that CsA nephropathy was associated with marked increase in apoptosis of tubular and interstitial cells. Fas may be an important mediator of tubular apoptosis induced by CsA. Enalapril and Losartan are effective on decreasing the number of tubular and interstitial apoptosis cells and expression of tubular Fas antigen.