Gas6 Induces Mesangial Cell Proliferation via Latent Transcription Factor STAT3

Motoko Yanagita,Atsushi Fukatsu,Toru Kita,Toshio Doi,Toru Nakano,Hidenori Arai,Kensaku Mizuno,Kazumasa Ohashi

doi:10.1074/jbc.m107488200

Abstract

Mesangial cell proliferation is essential for the pathogenesis and progression of glomerular disease. Previously, we showed that Gas6 plays a pivotal role in mesangial cell proliferation in vitro and in vivo. In the present study, we identified downstream targets of Gas6 signaling to examine the role in mesangial cell proliferation in vitro and in vivo. We found that Gas6 tyrosine phosphorylates STAT3 (signal transducers and activators of transcription) with concomitant translocation to the nucleus and induces STAT3-dependent transcriptional activation in cultured mesangial cells. Expressing dominant negative STAT3 inhibited Gas6-mediated transcriptional activation of STAT3 and abolished Gas6-induced mesangial cell proliferation. In a model of mesangial proliferative glomerulonephritis, STAT3 is phosphorylated in mesangial cells, and its phosphorylation peaks at day 8 after the injection of anti-Thy1.1 antibody. Inhibition of Gas6 by warfarin and the extracellular domain of its receptor, Axl, abolished phosphorylation of STAT3 in vivo. Thus, our in vitro and in vivo findings indicate that autocrine growth factor Gas6 induces mesangial cell proliferation via latent transcription factor STAT3. Therefore, STAT3 might be a new therapeutic target for kidney disease induced by mesangial proliferation.

Highlights

Mesangial cell proliferation is essential for the pathogenesis and progression of glomerular disease
Tyrosine Phosphorylation and Nuclear Translocation of STAT3 in Gas6-treated Mesangial Cells—To elucidate the role of STAT3 in Gas6-mediated mesangial cell proliferation, we examined whether Gas6 activates STAT3 by measuring its tyrosine phosphorylation and translocation to the nucleus in mouse mesangial cells
Gas6-induced tyrosine phosphorylation of STAT3 was abolished by the preincubation of Gas6 with Axl-Fc (Fig. 1C), indicating that the phosphorylation of STAT3 is through the binding of Gas6 to the cell surface Axl

Summary

Introduction

Mesangial cell proliferation is essential for the pathogenesis and progression of glomerular disease. Since the proliferation of mesangial cells is essential for the pathogenesis and progression of glomerular diseases, several studies have attempted to suppress mesangial cell proliferation by inhibiting specific mitogens, such as PDGF1 and basic fibroblast growth factor (4 – 6). We showed that Gas is an autocrine growth factor for mesangial cells (9) and that warfarin and the extracellular domain of Axl (a receptor for Gas6) abolish mesangial cell proliferation by specific inhibition of the Gas6-mediated pathway in experimental glomerulonephritis (10). Administration of these agents abolishes the induction of PDGF-B in Thy GN. This study reveals the crucial role of STAT3 activation in the pathogenesis of experimental glomerulonephritis

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Results

Conclusion