title: Mineralocorticoid receptor antagonist spironolactone prevents pig serum-induced hepatic fibrosis in rats.
abstract: Mineralocorticoid receptor (MR) antagonist spironolactone (SPL) is an effective agent for prevention of cardiovascular injury. However, whether and how SPL ameliorates hepatic fibrosis in rats is unknown. Pig serum (PS) (0.5 mL, twice a week, ip) or vehicle-administered rats for 12 weeks were used as rats with hepatic fibrosis or control rats, respectively. Rats given PS were treated with SPL (50 mg/kg/day, sc) for 12 weeks. Hepatic fibrosis, using picro-sirius red staining and determination of hydroxyproline content, immunohistochemistries of alpha-smooth muscle actin (alpha-SMA)-positive hepatic stellate cells (HSCs), Na/H exchange isoform-1 (NHE-1) protein, CYP11B2 aldosterone synthase protein for liver tissues, and plasma aldosterone concentrations were compared among the 3 groups of rats. Rats given PS alone exhibited hepatic fibrosis as well as increases in the number of the alpha-SMA-positive HSCs and NHE-1 protein expression in HSCs and hepatocytes, all of which were suppressed by SPL. Rats given PS alone revealed increased CYP11B2 protein expression in HSCs and hepatocytes, which was not inhibited by SPL. Plasma aldosterone concentrations were significantly greater in rats given PS and SPL than in control rats and rats given PS alone, although they were not different between control rats and rats given PS alone. PS-induced hepatic fibrosis together with HSC activation and NHE-1 protein expression occurs via MRs, and SPL ameliorates hepatic fibrosis presumably via the inhibition of HSC activation and NHE-1 protein expression in PS-induced liver injuries. The aldosterone produced in the injured liver contributes to the PS-induced hepatic fibrosis.
authors.affiliation: Divisions of Endocrinology & Metabolism and Nephrology, Department of Internal Medicine, Jichi Medical School, Minamikawachi, Tochigi, Japan. genrfjs@attglobal.net
authors.forename: Genro
authors.initials: G
authors.lastname: Fujisawa
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Muto
authors.forename: Koji
authors.initials: K
authors.lastname: Okada
authors.forename: Eiji
authors.initials: E
authors.lastname: Kusano
authors.forename: Shun
authors.initials: S
authors.lastname: Ishibashi
mesh_terms: D000199:Actins / Q000378:metabolism; D000450:Aldosterone / Q000378:metabolism*; D000818:Animals; D019405:Cytochrome P-450 CYP11B2 / Q000378:metabolism; D006909:Hydroxyproline / Q000378:metabolism; D007728:Kupffer Cells / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018161:Receptors, Mineralocorticoid / Q000187:drug effects*; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism; D013148:Spironolactone / Q000494:pharmacology*; D013552:Swine
chemical_list: D000199:Actins; D000450:Aldosterone; D019405:Cytochrome P-450 CYP11B2; D006909:Hydroxyproline; D000451:Mineralocorticoid Receptor Antagonists; D018161:Receptors, Mineralocorticoid; D017923:Sodium-Hydrogen Exchangers; D013148:Spironolactone; C513110:Slc9a2 protein, rat; C498862:Acta2 protein, rat