Preventive and therapeutic effects of angiotensin II type 1 receptor blocker on hepatic fibrosis induced by bile duct ligation in rats.
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.
Ueki
Masaru
M
Division of Medicine and Clinical Science, Department of Multidisciplinary Internal Medicine, Faculty of Medicine, Tottori University, 36-1 Nishimachi, Yonago, Japan.
Koda
Masahiko
M
Yamamoto
Satoru
S
Matsunaga
Yoshiko
Y
Murawaki
Yoshikazu
Y
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
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