title: The effects of the selective mineralocorticoid receptor antagonist eplerenone on hepatic fibrosis induced by bile duct ligation in rat.
abstract: The aim of this study was to examine the effects of eplerenone on hepatic fibrosis induced by bile duct ligation (BDL) in rat. Low- (1.0 mg/kg body weight, BW) and high- (4.0 mg/kg BW) dose eplerenone was administered orally for 21 days immediately following BDL. Fibrosis was assessed by measuring the fibrotic area after Sirius red staining. Immunostaining for alpha-smooth muscle actin (SMA), 4-hydroxy-2-nonenal (4-HNE) and 8-hydroxy-2-deoxyguanosine (8-OHdG) was also carried out. Gene expression levels of procollagen-I, transforming growth factor-beta1 (TGF-beta1), connective tissue growth factor (CTGF), tissue inhibitor of metalloproteinases-1 (TIMP-1) and matrix metalloproteinase-13 (MMP-13) in the liver were examined by real-time reverse transcriptase polymerase chain reaction. Plasma angiotensin II (ATII) concentration was measured via radioimmunoassay. The area of hepatic fibrosis and alpha-SMA positivity in the high-dose group was significantly decreased compared with that in the BDL group, but not in the low-dose group. 8-OHdG-positive cells in the low- and high-dose groups were significantly decreased compared with those in the BDL group. Immunostaining of 4-HNE in the high-dose group was significantly lower compared with that in the BDL group. Furthermore, TIMP-1 mRNA levels in the low- and high-dose groups were lower than that in the BDL group. The expression of TGF-beta1, CTGF, procollagen-1 and MMP-13 showed no differences. Plasma ATII concentration in the high-dose group was significantly decreased. Eplerenone attenuated the development of BDL-induced hepatic fibrosis by reducing oxidative stress, suppressing activated hepatic stellate cells and decreasing plasma ATII levels. Eplerenone may prove useful as an alternative treatment for antifibrosis therapy.
authors.affiliation: Division of Medicine and Clinical Science, Department of Multidisciplinary Internal Medicine, Faculty of Medicine, Tottori University, Yonago 683-8504, Japan.
authors.forename: Tomomitsu
authors.initials: T
authors.lastname: Matono
authors.forename: Masahiko
authors.initials: M
authors.lastname: Koda
authors.forename: Shiho
authors.initials: S
authors.lastname: Tokunaga
authors.forename: Takaaki
authors.initials: T
authors.lastname: Sugihara
authors.forename: Masaru
authors.initials: M
authors.lastname: Ueki
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Murawaki
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D001652:Bile Ducts / Q000187:drug effects / Q000601:surgery*; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D000077545:Eplerenone; D005786:Gene Expression Regulation / Q000187:drug effects; D006909:Hydroxyproline / Q000378:metabolism; D007150:Immunohistochemistry; D008026:Ligation; D015227:Lipid Peroxidation / Q000187:drug effects; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists; D018384:Oxidative Stress / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013148:Spironolactone / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000447:Aldehydes; D000451:Mineralocorticoid Receptor Antagonists; D012333:RNA, Messenger; D013148:Spironolactone; D000077545:Eplerenone; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003849:Deoxyguanosine; C027576:4-hydroxy-2-nonenal; D006909:Hydroxyproline