Injury-induced fibroblast-to-myofibroblast differentiation is a key event of renal fibrosis. YAP, a transcriptional coactivator, plays an important role in fibroblast activation and Smad transcriptional activity to promote TGF-β-induced differentiation from fibroblasts to myofibrolasts. 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. The MST1/2 and YAP expression levels increased in PDGFRα+ cells of obstructed kidneys following the increase of TGF-β and renal fibrosis after UUO. The PDGFRα+ cells-specific knockout of Mst1/2 in mice increased UUO-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 indicated that MST1/2 is a negative-feedback signal of TGF-β-induced fibroblast differentiation.

Renal fibrosis is a hallmark of chronic kidney disease (CKD) and a common manifestation of end-stage renal disease that is associated with multiple types of renal insults and functional loss of the kidney. Unresolved renal inflammation triggers fibrotic processes by promoting the activation and expansion of extracellular matrix-producing fibroblasts and myofibroblasts. Growing evidence now indicates that diverse T cells and macrophage subpopulations play central roles in the inflammatory microenvironment and fibrotic process. The present review aims to elucidate the role of CD8+ T cells in renal fibrosis, and identify its possible mechanisms in the inflammatory microenvironment.