Role of G protein-coupled estrogen receptor 1 in modulating transforming growth factor-β stimulated mesangial cell extracellular matrix synthesis and migration.

Estrogen has been demonstrated to exert beneficial effects on kidney; however, the role of G protein-coupled estrogen receptor 1 (GPER) is still uncertain. In the present study, we investigated the effect of 17β-estradiol and GPER agonist Fulvestrant on extracellular matrix production under transforming growth factor-β1 (TGF-β1) stimulation in human and rat mesangial cells. As a result, 17β-estradiol and Fulvestrant inhibit TGF-β1-induced type IV collagen and fibronectin expression in a dose-dependent manner, by suppressing acute Smad2/3 phosphorylation and Smad4 complex formation. Furthermore, estrogen and Fulvestrant also down-regulate Smad signaling by promoting ubiquitin/proteasome-dependent Smad2 degradation. These effects could be abrogated by receptor antagonist G-15 or GPER gene knockdown. GPER is also required for estrogen and Fulvestrant to regulate mesangial cell migration in response to TGF-β1. To conclude, GPER is crucial in modulating glomerular mesangial cell function including extracellular matrix production and migration.