title: Preventive and therapeutic effects of angiotensin II type 1 receptor blocker on hepatic fibrosis induced by bile duct ligation in rats.
abstract: 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.affiliation: Division of Medicine and Clinical Science, Department of Multidisciplinary Internal Medicine, Faculty of Medicine, Tottori University, 36-1 Nishimachi, Yonago, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Ueki
authors.forename: Masahiko
authors.initials: M
authors.lastname: Koda
authors.forename: Satoru
authors.initials: S
authors.lastname: Yamamoto
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Matsunaga
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Murawaki
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use*; D000818:Animals; D001562:Benzimidazoles / Q000627:therapeutic use*; D001713:Biphenyl Compounds; D002478:Cells, Cultured; D003135:Common Bile Duct / Q000601:surgery; D055513:Connective Tissue Growth Factor; D004797:Enzyme-Linked Immunosorbent Assay; D005500:Follow-Up Studies; D015870:Gene Expression; D006909:Hydroxyproline / Q000378:metabolism; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism; D018969:Insulin-Like Growth Factor Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008026:Ligation; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D016133:Polymerase Chain Reaction; D012313:RNA / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D013777:Tetrazoles / Q000627:therapeutic use*; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; C526316:CCN2 protein, rat; D017874:Immediate-Early Proteins; D018969:Insulin-Like Growth Factor Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; D013777:Tetrazoles; D053773:Transforming Growth Factor beta1; D055513:Connective Tissue Growth Factor; D012313:RNA; D006909:Hydroxyproline; C081643:candesartan