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Mechanism of inhibitory effect of warfarin on mesangial cell proliferation
1Department of Geriatric Medicine, Graduate School of Medicine, Faculty of Medicine, Kyoto University, Japan.
Abstract:
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.
Insights
Warfarin inhibits mesangial cell proliferation by blocking vitamin K-dependent growth factor Gas6. This finding reveals a new therapeutic strategy for glomerular diseases by targeting Gas6 gamma-carboxylation.
Area of Science:
- Nephrology
- Cell Biology
- Pharmacology
Background:
- Mesangial cell proliferation is a key feature of glomerular diseases.
- The mechanism of warfarin's effect on mesangial proliferation is not fully understood.
Purpose of the Study:
- To investigate if warfarin inhibits mouse mesangial cell proliferation.
- To explore the role of Gas6 (growth arrest-specific 6) in this process.
Main Methods:
- Examined Gas6 and Axl expression in mesangial cells.
- Assessed the effects of exogenous Gas6 on cell proliferation and signaling pathways.
- Investigated the impact of warfarin and vitamin K on endogenous Gas6 activity and cell proliferation.
Main Results:
- Gas6 and its receptor Axl are expressed in mesangial cells.
- Exogenous Gas6 promotes mesangial cell proliferation via Axl and ERK signaling.
- Warfarin inhibited proliferation stimulated by endogenous factors in conditioned medium, an effect reversed by vitamin K.
- Warfarin likely inhibits mesangial proliferation by interfering with Gas6 gamma-carboxylation.
Conclusions:
- Gas6 acts as an endogenous mitogen in mesangial cells.
- Warfarin's anti-proliferative effect on mesangial cells is mediated through the inhibition of Gas6 gamma-carboxylation.
- This research offers insights into glomerular disease regulation and potential new therapeutic targets.