Large-conductance and Ca2+-activated K+ (
BK) channels are expressed in human hepatic stellate cells (HSCs), where they have roles in normal hepatic microcirculation, as well as in
portal hypertension in
liver cirrhosis through the regulation of contractility in activated HSCs. Nevertheless, whether
BK channel activity exerts protective effects against aberrant HSC activation and hepatic
fibrosis is unknown. Here, we report that
BK channels are expressed in activated primary rat HSCs as well as in a human HSC line. Moreover, whole-cell K+ currents recorded from activated HSCs were markedly increased by exposure to
rottlerin, a
BK channel-specific activator, but were inhibited by treatment with the
BK channel-specific inhibitor,
paxilline, suggesting that
BK channels are functional in activated HSCs. Overexpression but not downregulation of the
BK channel pore-forming alpha subunit, KCNMA1, led to reduced migration and
collagen expression in activated HSCs. Consistently,
rottlerin treatment suppressed the fibrogenic cell function both in vitro and in CCl4-induced
liver fibrosis in vivo. Microarray and pathway analysis, combined with a
luciferase reporter assay and western blotting, further showed that
rottlerin treatment led to a significant downregulation of the profibrotic TGFβ1/SMAD3 and JAK/STAT3 signaling pathways, both in vitro and in vivo. Our findings not only link
BK channel function to profibrotic signaling pathways, but also provide evidence that
BK channel activation represents a promising therapeutic strategy for the treatment of
liver fibrosis.