坎地沙坦对肝纤维化大鼠的干预作用及其分子机制

Intervention effect of candesartan on rats with liver fibrosis and its molecular mechanism

目的分析血管紧张素受体拮抗剂坎地沙坦对肝纤维化大鼠的干预效果及其分子机制。方法将40只SD大鼠随机分为对照组、模型组和坎地沙坦高、中、低剂量组,每组8只。除对照组外,其他组采用四氯化碳诱导肝纤维化大鼠模型。从造模第5周开始,坎地沙坦高、中、低剂量组分别每日给予坎地沙坦20 mg/kg、10 mg/kg和5 mg/kg灌胃治疗,而对照组与模型组给予生理盐水灌胃。干预结束后,检测各组大鼠血清ALT和AST水平,取肝组织观察组织学变化并采用Ishak法评价肝纤维化程度;检测肝组织中Ⅰ型胶原蛋白和α平滑肌肌动蛋白(α-SMA)的mRNA及蛋白表达情况。结果(1)模型组肝纤维化Ishak评分高于对照组,而坎地沙坦高剂量组评分低于模型组(均P<0.05)。(2)模型组大鼠血清AST、ALT水平高于对照组,而坎地沙坦各剂量组血清ALT水平均低于模型组,且坎地沙坦高、中剂量组血清ALT水平低于低剂量组(均P<0.05)。(3)模型组肝组织Ⅰ型胶原蛋白和α-SMA的mRNA和蛋白表达水平均高于对照组,而坎地沙坦各剂量组上述指标均低于模型组,且坎地沙坦高剂量组的Ⅰ型胶原蛋白和α-SMA蛋白表达水平在坎地沙坦各剂量组中最低(均P<0.05)。结论血管紧张素受体拮抗剂坎地沙坦能够通过抑制肝星状细胞的激活改善肝纤维化大鼠的肝功能、降低肝纤维化程度,以高剂量(20 mg/kg)的干预效果最明显,其分子机制可能与该药物下调肝组织α-SMA和Ⅰ型胶原蛋白的表达有关。

Objective To analyze the intervention effect and its molecular mechanism of angiotensin receptor blocker candesartan on liver fibrosis rats.Methods Forty SD rats were randomized to control group,model group,high-dose candesartan group,medium-dose candesartan group or low-dose candesartan group,with eight rats in each group.Except the control group,a rat model of carbon tetrachloride-induced liver fibrosis was developed in the remaining groups.From the fifth week of modeling,the high-,medium-and low-dose candesartan groups were intragastrically administrated candesartan daily of 20 mg/kg,10 mg/kg and 5 mg/kg,respectively,while the control group and the model group were intragastrically administrated normal saline.At the end of intervention,serum ALT and AST levels of rats were determined in all groups,and liver tissues were harvested for histological changes observation and assessment of liver fibrosis degree by Ishak score.The mRNA and protein expression of liver tissue collagen type Ⅰ and alpha-smooth muscle actin(α-SMA)was measured.Results(1)The Ishak score of liver fibrosis was higher in the model group than in the control group,but was lower in the high-dose candesartan group than in the model group(all P<0.05).(2)Serum AST and ALT levels in the model group were higher than those in the control group,but serum ALT level was decreased in all candesartan groups than in the model group,and the high-and medium-dose candesartan groups possessed a lower serum ALT level as compared with the low-dose candesartan group(all P<0.05).(3)The mRNA and protein expression levels of collagen type Ⅰ andα-SMA in liver tissues were elevated in the model group than in the control group,but were reduced in all candesartan groups than in the model group,and among all candesartan groups,the high-dose candesartan group reported the lowest protein expression levels of collagen type Ⅰ and α-SMA(all P<0.05).Conclusion Angiotensin receptor blocker candesartan can improve liver function and reduce the degree of liver fibrosis in rats with liver fibrosis by inhibiting the activation of hepatic stellate cells,and the high-dose(20 mg/kg)candesartan achieves the most significant intervention effect.The molecular mechanism may be related to down-regulating the expression ofα-SMA and collagen type Ⅰ proteins in liver tissues by candesartan.