阿利吉仑对大鼠急性肝衰竭的保护作用及机制研究

Study on the Protective Effect and Mechanism of Aliskiren on Acute Liver Failure in Rats

目的探讨阿利吉仑对急性肝衰竭的保护作用及其分子机制。方法将30只健康SD大鼠按随机数字表法分为正常对照组、肝衰竭组和阿利吉仑组。通过D-氨基半乳糖(D-galactosamine,D-GalN)/脂多糖(lipopolysaccharide,LPS)联合腹腔注射诱导急性肝衰竭模型。阿利吉仑组造模前30min腹腔注射阿利吉仑(25mg/kg)。所有实验大鼠造模后10h统一处死采样,检测大鼠血清的ALT、AST、LDH、ALP及TNF-α、IL-6、TGF-β1、AngⅡ、Ang(1-7)水平,观察肝脏组织中炎症坏死及细胞凋亡水平,分析大鼠肝脏组织GRP78、CHOP分子的表达水平。结果阿利吉仑干预可以明显降低ACE-AngⅡ-AT1R轴激活水平。与肝衰竭组比较,阿利吉仑组大鼠血清的ALT、AST、LDH、ALP水平及TNF-α、IL-6、TGF-β1水平均明显下降,阿利吉仑组大鼠肝脏组织炎症损伤明显减轻,肝细胞凋亡指数明显下降。阿利吉仑组大鼠的肝脏组织中ERS相关因子GRP78和CHOP的表达水平较肝衰竭组明显下调。结论阿利吉仑通过阻断RAS,能够明显减轻急性肝衰竭进程中的肝脏炎症,减少肝细胞的凋亡,其保护作用可能与抑制内质网应激有关。

Objective To investigate the protective effect of aliskiren on acute liver failure and its molecular mechanism.Methods 30 healthy SD rats were randomly divided into normal control group,liver failure group and aliskiren group.The liver failure group was given intraperitoneal injection of D-GalN combined with LPS to establish an ALF model.The aliskiren group was intraperitoneally injected with aliskiren(25mg/kg)30 minutes before the injection of D-GalN and LPS.All experimental rats were sacrificed 10 hours after modeling.The level of ALT,AST,LDH,ALP and TNF-α,IL-6,TGF-β1,AngⅡ,Ang(1-7)were detectied.The liver pathologic changes and the apoptosis index in liver tissue were observed.The expression levels of GRP78 and CHOP in rat liver tissue were detected.Results The activation of ACE-AngⅡ-AT1R axis was reduced by aliskiren.Compared with liver failure group,the level of ALT,AST,LDH,ALP and TNF-α,IL-6,TGF-β1 of the aliskiren group significantly decreased,and the liver tissue inflammatory injury was significantly reduced,and the hepatocyte apoptosis index significantly decreased.The expression levels of ERS-related factors GRP78 and CHOP in the liver tissue of the aliskiren group were significantly down-regulated compared with liver failure group.Conclusion Aliskiren can significantly reduce liver inflammation and liver cell apoptosis in the process of acute liver failure by blocking RAS,and its protective effect may be related to the inhibition of endoplasmic reticulum stress.