Preventive and therapeutic effects of angiotensin II type 1 receptor blocker on hepatic fibrosis induced by bile duct ligation in rats

• Published in: Journal of gastroenterology 2006-10, Vol.41 (10), p.996-1004
• Main Authors: Ueki, Masaru, Koda, Masahiko, Yamamoto, Satoru, Matsunaga, Yoshiko, Murawaki, Yoshikazu
• Format: Article
• Language: English
• Subjects: Actin; Angiotensin; Angiotensin II; Angiotensin II Type 1 Receptor Blockers - therapeutic use; Animals; Benzimidazoles - therapeutic use; Bile ducts; Biphenyl Compounds; Cells, Cultured; Cholestasis; Collagen; Collagen (type I); Common Bile Duct - surgery; Connective Tissue Growth Factor; Connective tissues; Enzyme-Linked Immunosorbent Assay; Fibrosis; Follow-Up Studies; Gallbladder diseases; Gene Expression; Growth factors; Hydroxyproline; Hydroxyproline - metabolism; Immediate-Early Proteins - genetics; Immediate-Early Proteins - metabolism; Insulin-Like Growth Factor Binding Proteins; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - metabolism; Ligation; Lipid peroxidation; Liver; Liver - metabolism; Liver - pathology; Liver Cirrhosis, Experimental - etiology; Liver Cirrhosis, Experimental - metabolism; Liver Cirrhosis, Experimental - prevention & control; Male; Oral administration; Polymerase Chain Reaction; Rats; Rats, Wistar; RNA - genetics; RNA-directed DNA polymerase; Smooth muscle; Stellate cells; Tetrazoles - therapeutic use; Thiobarbituric acid; Transforming Growth Factor beta1 - genetics; Transforming Growth Factor beta1 - metabolism; Transforming growth factor-b1; Treatment Outcome
• ISSN: 0944-1174; 1435-5922
• DOI: 10.1007/s00535-006-1891-1

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. 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. 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. 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.