Preventative and therapeutic effects of perindopril on hepatic fibrosis induced by bile duct ligation in rats

Abstract

The aim of this study was to examine the preventative and therapeutic effects of an angiotensin-converting enzyme inhibitor, perindopril, on cholestasis-induced liver fibrosis. Perindopril was administered orally for 21 days immediately after bile duct ligation at a dose of 2 mg/kg in order to evaluate the preventative effects, and for 21 days starting 3 weeks after bile duct ligation at doses of 2 and 8 mg/kg in order to evaluate the therapeutic effects. With regard to the preventative effects, perindopril reduced the hepatic hydroxyproline content by 33%, collagen-I mRNA by 38%, α-smooth muscle actin (α-SMA)-positive cells by 46%, α-SMA mRNA by 40%, transforming growth factor-β1 (TGF-β1) mRNA by 21% and connective tissue growth factor (CTGF) mRNA by 27%. With regard to the therapeutic effects, at 2 mg/kg perindopril had no inhibitory effects on the progression of liver fibrosis, but at 8 mg/kg, it reduced hepatic hydroxyproline contents by 63%, collagen-I mRNA by 94%, TGF-β1 mRNA by 79%, CTGF mRNA by 97% and tissue inhibitor of metalloproteinase-1 mRNA by 87%. Significant decreases in the oxidative stress markers hepatic 4-hydroxy-2-nonenal and 8-hydroxy-2-deoxyguanosine were noted for perindopril administration at 8 mg/kg, but not at 2 mg/kg. In conclusion, perindopril had preventative and therapeutic effects on cholestasis-induced liver fibrosis through the inhibition of oxidative stress and/or the activation of hepatic stellate cells, thus suggesting the possible application of perindopril as an antifibrotic drug.