The regulatory role of AT 1 receptor on activated HSCs in hepat,c fibrogenesis,effects of RAS inhibitors on hepatic fibrosis induced by CCl_4  

作　　者：Hong Shan Wei Han Ming Lu Ding Guo Li Yu Tao Zhan Zhi Rong Wang Xin Huang Ji Lin Cheng Qin Fang Xu Department of Gastroenterology,Xinhua Hospital,Shanghai Second Medical University,Shanghai 200092,China 

出　　处：《World Journal of Gastroenterology》2000年第6期824-828,共5页世界胃肠病学杂志（英文版）

摘　　要：AIM To assess the effect of ACE inhibitor andAng Ⅱ type Ⅰ（AT1）receptor antagonist inpreventing hepatic fibrosis caused by CCl₄administration in rats;to investigate whether ornot there are expression of AT 1 receptors onhepatic stellate cells;and to observe the effectof Ang Ⅱ on proliferation and ECM synthesis ofcultured HSCs.METHODS Studies were conducted in maleSprague-Dawley rats.Except for thehepatofibrotic model group and the controlgroup,in three treated groups,either enalapril（5 mg/kg）,or Iosartan（10 mg/kg）,or enalapril+Iosartan were given to the fibrotic rats bydaily gavage,and saline vehicle was given tomodel and normal control rats.After 6 weeks,liver fibrosis was assessed directly by hepaticmorphometric analysis,which has beenconsidered the gold standard for thequantification of fibrosis.The expressions of AT1 receptors and（α-mooth muscle actin,α-SMA）in liver tissue or isolated hepatic stellate cells（HSCs）were detected by immunohistochemicaltechniques.The effect of Ang Ⅱ on HSCproliferation was determined by MTT method.Effect of Ang Ⅱ on collagen synthesis of HSCswas determined by ³H-proline incorporation.RESULTS Contrasted to the fibrosis in rats ofthe model group,groups of rats treated with either enalapril or Iosartan,or a combination oftwo drugs showed a limited expansion of theinterstitium（4.23±3.70 vs 11.22±4.79,P【0.05）,but no difference was observedamong three treated groups（5.38±3.43,4.96±2.96,4.23±2.70,P】0.05）.Expression of AT 1receptors was found in fibrotic interstitium offibrotic rats,whereas in normal control rats theywere limited to vasculature only to a very slightdegree.AT 1 receptors were also expressed onactivated HSCs in the culture.At concentrationsfrom 10^-9to 10^-5mol/L,Ang Ⅱ stimulated HSCproliferation in culture in a dose-dependentmanner.Increasing Ang Ⅱ concentrationsproduced corresponding increases in ³H-prolineincorporation.Differences among groups were significant.CONCLAIM To assess the effect of ACE inhibitor and Ang Ⅱ type Ⅰ(AT1)receptor antagonist in preventing hepatic fibrosis caused by CCl_4 administration in rats;to investigate whether or not there are expression of AT 1 receptors on hepatic stellate cells;and to observe the effect of Ang Ⅱ on proliferation and ECM synthesis of cultured HSCs. METHODS Studies were conducted in male Sprague-Dawley rats.Except for the hepatofibrotic model group and the control group,in three treated groups,either enalapril (5 mg/kg),or Iosartan(10 mg/kg),or enalapril +Iosartan were given to the fibrotic rats by daily gavage,and saline vehicle was given to model and normal control rats.After 6 weeks, liver fibrosis was assessed directly by hepatic morphometric analysis,which has been considered the gold standard for the quantification of fibrosis.The expressions of AT 1 receptors and(α-mooth muscle actin,α-SMA) in liver tissue or isolated hepatic stellate cells (HSCs)were detected by immunohistochemical techniques.The effect of Ang Ⅱ on HSC proliferation was determined by MTT method. Effect of Ang Ⅱ on collagen synthesis of HSCs was determined by ~3H-proline incorporation. RESULTS Contrasted to the fibrosis in rats of the model group,groups of rats treated with either enalapril or Iosartan,or a combination of two drugs showed a limited expansion of the interstitium(4.23±3.70 vs 11.22±4.79, P<0.05),but no difference was observed among three treated groups(5.38±3.43,4.96± 2.96,4.23±2.70,P>0.05).Expression of AT 1 receptors was found in fibrotic interstitium of fibrotic rats,whereas in normal control rats they were limited to vasculature only to a very slight degree.AT 1 receptors were also expressed on activated HSCs in the culture.At concentrations from 10^(-9)to 10^(-5)mol/L,Ang Ⅱ stimulated HSC proliferation in culture in a dose-dependent manner.Increasing Ang Ⅱ concentrations produced corresponding increases in ~3H-proline incorporation.Differences among groups were significant.CONCLUSION Angiotensin-converting enzyme i

关 键 词：RENIN-ANGIOTENSIN system LIVER cirrhosis ENALAPRIL extracellular matrix immunohistochemistry LOSARTAN liver/injuries 

分 类 号：R575.2[医药卫生—消化系统]