培哚普利和缬沙坦对肝纤维化大鼠TGF β1及其Ⅱ型受体mRNA与Smad3、7表达的影响

目的观察培哚普利和缬沙坦抗大鼠肝纤维化的疗效和对转化生长因子β1(TGFβ1)及其Ⅱ型受体(TGFβ1RⅡ)mRNA与Smad3、smad17的影响。方法大鼠随机分为止常对照组，模型组、培哚普利治疗组和缬沙坦治疗组。四氯化碳皮下注射诱导大鼠肝纤维化模型，治疗组于造模第4周开始分别予以培哚普利和缬沙坦灌胃。采用RT-PCR检测肝组织TGFβ1与TGFβ1RⅡ mRNA；免疫组织化学技术检测TGFβ1、Smad3及smad7在肝内的表达及定位，检测肝组织病理改变，检测肝组织羟脯氢酸和血清透明质酸。结果与模型组大鼠比较，经培哚普利或缬沙坦治疗大鼠肝内TGFβ1与TGFβ1RⅡ mRNA表达明显下降、以及smad3蛋白表达明显降低，而Smad7的表达增加。TGFβ1与Smad3的免疫阳性反应信号主要位于纤维间隔中的细胞浆，Smad7主要在肝细胞浆表达，上述物质在两种药物组之间表达差异无显著性。培哚普利或缬沙坦治疗后肝组织羟脯氨酸及血清透明质酸含量较模型组显著降低；肝小叶结构均趋于正常，纤维间隔明显变溥。结论培哚普利或缬沙坦均能有效地减轻肝纤维化大鼠的肝脏损伤及纤维化程度，其机制可能与直接或间接抑制肝内TGFβ1与TGFβ1RⅡ mRNA及Smad3表达，并促进Smad7表达有关。

Effects of perindopril and valsartan on the expression of TGF β1 and TGF β receptor Ⅱ mRNA,Smad3 and Smad7 in experimental hepatic fibrotic rats

OBJECTIVE: To investigate the therapeutic effects of perindopril, an angiotensin-converting enzyme inhibitor, and valsartan, an angiotensin II receptor blocker on TGFbeta1 and TGFbeta receptor II mRNA, Smad3 and Smad7 on rat liver fibrosis. METHODS: 60 Wistar rats were randomly divided into four groups (each group, n=15). Group 1 rats were not treated and served as healthy controls. The rats of groups 2,3,and 4 were injected with CCl(4) which induced liver fibrosis. After four weeks, group 3 rats started a treatment of perindopril, and group 4 rats with valsartan. All rats were sacrificed at the eighth week and their blood and livers were collected for analysis. The effects of perindopril and valsartan were evaluated by the levels of transforming growth factor-beta1 (TGFb1), and TGF receptor (TGFb1RII) mRNA in liver tissues by RT-PCR, the expressions and sites of TGFb1, Smad3 and Smad7 in liver tissue by immunohistochemical staining. The liver histopathology was also examined with HE staining, and the hydroxyproline in the liver and serum hyaluronic acid (HA) were examined using biochemsitry and RIA. RESULTS: Compared with the control group, the levels of TGFb1, TGFb1RII mRNA and the expression Smad3 were significantly decreased in the two treated groups, and the expression of Smad7 was also remarkably increased in the livers of rats treated with perindopril or valsartan. The histological changes of fibrosis, the hydroxyproline in the livers and HA were also improved in the treated rats. CONCLUSION: Perindopril and valsartan have a protective effect on liver injury and can inhibit hepatic fibrosis induced by CCl(4) in rats. Their mechanisms may be associated with their effects of down-regulating TGFb1, TGFb1RII mRNA and smad3, and up-regulating Smad7 which then resulted in suppressing the activation of hepatic stellate cells.