坎地沙坦对肝纤维化大鼠血管紧张素转化酶2表达的影响

Effect of candesartan on angiotensin converting enzyme 2 in rats with hepatic fibrosis

目的旨在观察血管紧张素Ⅱ1型受体拮抗剂(ARB)坎地沙坦对四氯化碳(CCl4)大鼠肝纤维化模型的疗效及大鼠肝组织血管紧张素转化酶2(ACE2)表达的影响。方法 42只雄性Wistar大鼠随机分为3组,正常对照组12只,模型组15只,坎地沙坦治疗组15只。除对照组外,给予大鼠首次皮下注射40%CCl4油剂5mL/kg,以后每次皮下注射40%CCL42mL/kg,每周2次。正常对照组给予相同剂量的油剂皮下注射。预防治疗组从实验第1天开始给予坎地沙坦(4mg.kg-1.d-1)灌胃,直至实验结束,共8周。分别于42d(6周)及56d(8周)时,测定各组体质量和门脉压力后,分别杀死6只大鼠,留取血及肝组织标本备用。分离血清测丙氨酸氨基转移酶(ALT),通过苏木素-伊红(HE)及Masson染色观察各组肝纤维化的程度,采用免疫组织化学染色测定ACE2表达情况。结果与对照组相比,模型组体质量降低(P<0.05),血清ALT升高(P<0.05),而预防治疗组体质量增加,ALT水平下降,差异有统计学意义(P<0.05),模型组门脉压力升高,与对照组比较差异有统计学意义(P<0.05),治疗组的门脉压力下降(P<0.05)。ACE2免疫组织化学结果表明:与正常对照组相比,模型组肝组织中ACE2阳性表达增强(P<0.05),坎地沙坦治疗组ACE2表达较模型组明显增高(P<0.05)。结论血管紧张素(Ang)Ⅱ1型受体拮抗剂坎地沙坦具有良好的抗肝纤维化作用,其机制是坎地沙坦可增加肝组织ACE2表达,激活ACE2-Ang-(1-7)-Mas轴,促进Ang-(1-7)的生成增多,从而发挥其抗肝纤维化的作用。

Objective This study is an attempt to explore the curative effects of angiotensin Ⅱ type 1（AT1） receptor blocker candesartan on hepatic fibrosis induced by chronic carbon tetrachloride（CCl4） in rats and to observe candesartan＇ impacts on ACE2.Methods Forty-two Wistar rats was randomly divided into three groups：control group（n=12）,Model group（n=15） and treatment group（n=15）.Except rats in control group,all were given intraperitoneal injections of 40 % CCl4,and from the first day of the intraperitoneal injection,rats in treatment groups were given candesartan for 8 weeks by gastric gavage.The liver tissues were obtaind from the control group,the model group and the candesartan treated group in different period respectively.Histopathological study of liver tissue was done with hematoxylin-eosin（HE） and Masson trichrome staining.The expressions of ACE2 in different groups were measured by S-ABC immunohistochemistry,Blood samples were taken for detecting alanine aminotransferase（ALT）.Results Experimental rat hepatic fibrosis model induced by CCl4 was established.The expressions of ACE2 in liver tissues increased with the development of hepatic fibrosis（P0.05）,while candesartan induced ACE2 expression in hepatic fibrosis rats（P0.05）.Candesartan significantly attenuated the degree of hepatic fibrosis,reduced portal pressure（P0.05） and reduced ALT level（P0.05）.Conclusion The expressions of ACE2 in liver tissue increase with the development of hepatic fibrosis,and candesartan elevated ACE2 expression in hepatic fibrosis in rats,which might inhibit the liver fibrosis.