Mechanism of inhibitory effect of warfarin on mesangial cell proliferation

Because proliferation of mesangial cells is a hallmark of glomerular diseases, understanding the regulatory mechanism of mesangial proliferation is important for the treatment. Warfarin has long been used to treat glomerular diseases, although its mechanism of effect on mesangial proliferation has remained unknown. Therefore, this study was conducted to examine whether warfarin can inhibit mouse mesangial cell proliferation by focusing on Gas6, which has been shown to be activated by vitamin K-dependent gamma-carboxylation. In mesangial cells, Gas6 and its receptor Axl were expressed. In addition, exogenous Gas6 phosphorylated Axl, activated extracellular signal-regulated kinase, and stimulated [3H]-thymidine incorporation in mouse mesangial cells. This study also examined whether endogenous Gas6 stimulates mesangial proliferation. Conditioned medium (CM) from serum-starved mesangial cells could stimulate [3H]-thymidine incorporation and phosphorylate extracellular 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 factors in the CM are critical for mesangial proliferation. Addition of the extracellular domain of Axl to the CM inhibited its mitogenic effect on mesangial cells, suggesting that this vitamin K-dependent growth factor is Gas6. It is concluded that Gas6 is an endogenous mitogen in mesangial cells, and warfarin inhibits mesangial proliferation possibly by inhibiting gamma-carboxylation of Gas6. This study sheds light on the regulation of mesangial proliferation and may lead to a new therapeutic strategy for glomerular diseases.