BACKGROUND: The aim of this study was to examine the preventive and therapeutic effects of an angiotensin II type 1 receptor blocker, candesartan, on cholestasis-induced liver fibrosis. METHODS: Candesartan was administered orally for 21 days immediately after bile duct ligation to evaluate its preventive effect, and for 21 days starting 3 weeks after bile duct ligation to evaluate its therapeutic effect. Fibrosis was assessed by measuring hepatic hydroxyproline (Hyp) content. The activated hepatic stellate cells (HSCs) were assessed by alpha-smooth muscle actin (alpha-SMA) immunostaining. The gene expression of collagen I, transforming growth factor-beta1 (TGF-beta1), and connective tissue growth factor (CTGF) in the liver was examined by real-time reverse transcriptase-polymerase chain reaction. RESULTS: As a preventive effect, candesartan reduced the hepatic Hyp content by 36%, alpha-SMA-positive cells by 65%, hepatic TGF-beta1 content by 35%, and the expression of collagen I by 72%, TGF-beta1 by 67%, and CTGF mRNA by 69%. As a therapeutic effect, candesartan reduced the hepatic Hyp content by 48%, TGF-beta1 content by 54%, and the expression of collagen I by 47%, TGF-beta1 by 43%, and CTGF mRNA by 53%. Significant decreases in lipid peroxidation markers, hepatic thiobarbituric acid-reactive substance, and 4-hydroxy-2-nonenal were observed in candesartan-treated rats. CONCLUSIONS: Candesartan attenuated liver fibrosis via suppression of collagen I and TGF-beta1 expression, HSC activation, and lipid peroxidation protein, showing its preventive and therapeutic effects on cholestasis-induced liver fibrosis.
BACKGROUND: The aim of this study was to examine the preventive and therapeutic effects of an angiotensin II type 1 receptor blocker, candesartan, on cholestasis-induced liver fibrosis. METHODS: Candesartan was administered orally for 21 days immediately after bile duct ligation to evaluate its preventive effect, and for 21 days starting 3 weeks after bile duct ligation to evaluate its therapeutic effect. Fibrosis was assessed by measuring hepatic hydroxyproline (Hyp) content. The activated hepatic stellate cells (HSCs) were assessed by alpha-smooth muscle actin (alpha-SMA) immunostaining. The gene expression of collagen I, transforming growth factor-beta1 (TGF-beta1), and connective tissue growth factor (CTGF) in the liver was examined by real-time reverse transcriptase-polymerase chain reaction. RESULTS: As a preventive effect, candesartan reduced the hepatic Hyp content by 36%, alpha-SMA-positive cells by 65%, hepatic TGF-beta1 content by 35%, and the expression of collagen I by 72%, TGF-beta1 by 67%, and CTGF mRNA by 69%. As a therapeutic effect, candesartan reduced the hepatic Hyp content by 48%, TGF-beta1 content by 54%, and the expression of collagen I by 47%, TGF-beta1 by 43%, and CTGF mRNA by 53%. Significant decreases in lipid peroxidation markers, hepatic thiobarbituric acid-reactive substance, and 4-hydroxy-2-nonenal were observed in candesartan-treated rats. CONCLUSIONS: Candesartan attenuated liver fibrosis via suppression of collagen I and TGF-beta1 expression, HSC activation, and lipid peroxidation protein, showing its preventive and therapeutic effects on cholestasis-induced liver fibrosis.
Authors: G Paizis; R E Gilbert; M E Cooper; P Murthi; J M Schembri; L L Wu; J R Rumble; D J Kelly; C Tikellis; A Cox; R A Smallwood; P W Angus Journal: J Hepatol Date: 2001-09 Impact factor: 25.083
Authors: S Kim; K Ohta; A Hamaguchi; T Omura; T Yukimura; K Miura; Y Inada; Y Ishimura; F Chatani; H Iwao Journal: J Pharmacol Exp Ther Date: 1995-04 Impact factor: 4.030
Authors: Sadashiva S Karnik; Hamiyet Unal; Jacqueline R Kemp; Kalyan C Tirupula; Satoru Eguchi; Patrick M L Vanderheyden; Walter G Thomas Journal: Pharmacol Rev Date: 2015-10 Impact factor: 25.468
Authors: Yongzhong Wei; Suzanne E Clark; E Matthew Morris; John P Thyfault; Grace M E Uptergrove; Adam T Whaley-Connell; Carlos M Ferrario; James R Sowers; Jamal A Ibdah Journal: J Hepatol Date: 2008-04-22 Impact factor: 25.083