Gas6 regulates mesangial cell proliferation through Axl in experimental glomerulonephritis

Proliferation of mesangial cells Is a hallmark of glomerular disease, and u nderstanding its regulatory mechanism is clinically important. Previously, we demonstrated that the product of growth arrest-specific gene 6 (Gas6) st imulates mesangial cell proliferation through binding to its cell-surface r eceptor Axl in vitro, We also showed that warfarin and the extracellular do main of Axl conjugated with Fc portion of human IgG1 (Axl-Fc) inhibit mesan gial cell proliferation by interfering the Gas6/Axl pathway in vitro. In th e present study, therefore, we examined in vivo roles of Gasb and Axl in an experimental model of mesangial proliferative glomerulonephritis induced b y the injection of anti-Thy1.1 antibody (Thy1 GN). In Thy1 GN, expression o f Gas6 and Axl was markedly increased in glomeruli, and paralleled the prog ression of mesangial cell proliferation. Administration of warfarin or dail y injection of Axl-Fc inhibited mesangial cell proliferation, and abolished the induction of platelet-derived growth factor-B mRNA and protein in Thy1 GN, Moreover, the anti-proliferative effect of warfarin was achieved at lo wer concentrations than those in routine clinical use. These findings indic ate that the Gas6/Axl pathway plays a key role in mesangial cell proliferat ion in vivo, and could be a potentially important therapeutic target for th e treatment of renal disease.