Inhibition of the renin-angiotensin system attenuates the development of liver fibrosis and oxidative stress in rats

1. The present study was designed to investigate the potential antifibrotic and anti-oxidant effects of lisinopril, fosinopril and losartan in an experimental rat model of liver injury using carbon tetrachloride (CCl4). 2. First, the potential hepatoprotective dose of each drug was screened against CCl4-induced acute hepatotoxicity. Then, we chose the minimum hepatoprotective dose of each drug to further investigate the mechanisms involved in the hepatoprotection using a chronic model of hepatotoxicity induced by CCl4. 3. Liver function was assessed in addition to histopathological examination. Furthermore, oxidative stress markers (reduced glutathione (GSH) and lipid peroxides levels) and markers of fibrosis (hydroxyproline content and liver fibrosis area) were assessed. 4. It was found that treatment of animals with different drugs concomitantly with CCl4 significantly counteracted the changes in liver function induced by CCl4 (except fosinopril). In addition, the drugs ameliorated the histopathological changes induced by CCl4. All drugs significantly counteracted lipid peroxidation and GSH depletion (except fosinopril) compared with the CCl4-intoxicated group. Moreover, the drugs studied significantly reduced liver hydroxyproline levels and the area of fibrosis compared with the CCl4-intoxicated group. 5. In conclusion, the present study provides evidence for the hepatoprotective effect of lisinopril, fosinopril and losartan. Both lisinopril and losartan was found to have better hepatoprotective potential than fosinopril against CCl4-induced hepatotoxicity. These hepatoprotective effects can be explained on the basis of anti-oxidant and antifibrotic mechanisms, mainly enhancement of GSH and reduction of lipid peroxidation and fibrosis.