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

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-beta (TGF-beta)-induced differentiation from fibroblasts to myofibrolasts. Macrophage stimulating 1/2 (MST1/2), a negative regulator of YAP, also increases in fibroblasts by TGF-beta stimulation. Here, we examined whether MST1/2, as a negative regulator, attenuated YAP and TGF-beta/Smad signaling in fibroblasts to reduce fibrosis. MST1/2 and YAP expression levels increased in platelet-derived growth factor receptor-alpha (PDGFR alpha)(+) cells of obstructed kidneys following the increase of TGF-beta and renal fibrosis after unilateral ureteral obstruction. PDGFR alpha(+) cell-specific knockout of Mst1/2 in mice increased unilateral ureteral obstruction-induced myofibroblast accumulation and fibrosis. In cultured fibroblasts, TGF-beta increased YAP and promoted its nucleus entry, but a high dose and prolonged treatment of TGF-beta 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-beta-induced fibroblast differentiation. NEW & NOTEWORTHY Using a mouse model with macrophage stimulating 1/2 (Mst1/2) double knockout in PDGFR alpha(+) cells and an MST1/2 inhibitor, we demonstrated that MST1/2 acted as a negative feedback signal of transforming growth factor-beta-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.