Gas6 induces mesangial cell proliferation via latent transcription factor STAT3

Mesangial cell proliferation is essential for the pathogenesis and progress ion of glomerular disease. Previously, we showed that Gas6 plays a pivotal role in mesangial cell proliferation in vitro and in vivo. In the present s tudy, we identified downstream targets of Gas6 signaling to examine the rol e in mesangial cell proliferation in vitro and in vivo. We found that Gas6 tyrosine phosphorylates STAT3 (signal transducers and activators of transcr iption) with concomitant translocation to the nucleus and induces STAT3-dep endent transcriptional activation in cultured mesangial cells. Expressing d ominant negative STAT3 inhibited Gas6-mediated transcriptional activation o f 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 extracellu lar domain of its receptor, AxI, abolished phosphorylation of STAT3 in vivo . Thus, our in vitro and in vivo findings indicate that autocrine growth fa ctor Gas6 induces mesangial cell proliferation via latent transcription fac tor STAT3. Therefore, STAT3 might be a new therapeutic target for kidney di sease induced by mesangial proliferation.