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.