Mechanism of inhibitory effect of warfarin on mesangial cell proliferation

Citation
M. Yanagita et al., Mechanism of inhibitory effect of warfarin on mesangial cell proliferation, J AM S NEPH, 10(12), 1999, pp. 2503-2509
Citations number
23
Categorie Soggetti
Urology & Nephrology","da verificare
Journal title
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
ISSN journal
10466673 → ACNP
Volume
10
Issue
12
Year of publication
1999
Pages
2503 - 2509
Database
ISI
SICI code
1046-6673(199912)10:12<2503:MOIEOW>2.0.ZU;2-U
Abstract
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.