Because proliferation of mesangial cells is a hallmark of glomerular diseas
es, understanding the regulatory mechanism of mesangial proliferation is im
portant for the treatment. Warfarin has long been used to treat glomerular
diseases, although its mechanism of effect on mesangial proliferation has r
emained unknown. Therefore, this study was conducted to examine whether war
farin can inhibit mouse mesangial cell proliferation by focusing on Gas6, w
hich has been shown to be activated by vitamin K-dependent gamma-carboxylat
ion. In mesangial cells, Gas6 and its receptor Ax1 were expressed. In addit
ion, exogenous Gas6 phosphorylated Ax1, activated extracellular signal-regu
lated kinase, and stimulated [H-3]-thymidine incorporation in mouse mesangi
al cells. This study also examined whether endogenous Gas6 stimulates mesan
gial proliferation. Conditioned medium (CM) from serum-starved mesangial ce
lls could stimulate [3H]-thymidine incorporation and phosphorylate extracel
lular signal-regulated kinase, whereas CM in the presence of warfarin could
not. Simultaneous administration of vitamin K could cancel the inhibitory
effect of warfarin. These results suggest that vitamin K-dependent growth f
actors in the CM are critical for mesangial proliferation. Addition of the
extracellular domain of Ax1 to the CM inhibited its mitogenic effect on mes
angial cells, suggesting that this vitamin K-dependent growth factor is Gas
6. It is concluded that Gas6 is an endogenous mitogen in mesangial cells, a
nd warfarin inhibits mesangial proliferation possibly by inhibiting gamma-c
arboxylation of Gas6. This study sheds light on the regulation of mesangial
proliferation and may lead to a new therapeutic strategy for glomerular di
seases.