MST1/2 in PDGFRα+ cells negatively regulates TGF-β-induced myofibroblast accumulation in renal fibrosis

Abstract

Injury-induced fibroblast-to-myofibroblast differentiation is a key event of renal fibrosis. Yes-associated protein (YAP), a transcriptional coactivator, plays an important role in fibroblast activation and Smad transcriptional activity to promote transforming growth factor-β (TGF-β)-induced differentiation from fibroblasts to myofibrolasts. Macrophage stimulating 1/2 (MST1/2), a negative regulator of YAP, also increases in fibroblasts by TGF-β stimulation. Here, we examined whether MST1/2, as a negative regulator, attenuated YAP and TGF-β/Smad signaling in fibroblasts to reduce fibrosis. MST1/2 and YAP expression levels increased in platelet-derived growth factor receptor-α (PDGFRα)⁺ cells of obstructed kidneys following the increase of TGF-β and renal fibrosis after unilateral ureteral obstruction. PDGFRα⁺ cell-specific knockout of Mst1/2 in mice increased unilateral ureteral obstruction-induced myofibroblast accumulation and fibrosis. In cultured fibroblasts, TGF-β increased YAP and promoted its nucleus entry, but a high dose and prolonged treatment of TGF-β increased the MST1/2 activation to prevent YAP from entering the nucleus. Our results indicate that MST1/2 is a negative feedback signal of TGF-β-induced fibroblast differentiation.NEW & NOTEWORTHY Using a mouse model with macrophage stimulating 1/2 (Mst1/2) double knockout in PDGFRα⁺ cells and an MST1/2 inhibitor, we demonstrated that MST1/2 acted as a negative feedback signal of transforming growth factor-β-induced fibroblast differentiation. Furthermore, we demonstrated that Hippo-MST as a negative feedback signal can decrease the renal fibrosis process. This finding contributes to our understanding of the mechanism of coregulated renal remodeling after injury.

Keywords: Hippo signaling; fibroblast; macrophage stimulating 1/2; myofibroblast; renal fibrosis.