Yap/Taz Deletion in Gli+ Cell-Derived Myofibroblasts Attenuates Fibrosis

作者：Liang Ming, Michael Yu, Ruohan Xia, Ke Song, Jun Wang, Jinlong Luo, Guang Chen, Jizhong Cheng · 发表于：Journal of the American Society of Nephrology · 年份：2017 · DOI：10.1681/asn.2015121354 · 被引用次数：159 · 研究领域：Hippo pathway signaling and YAP/TAZ、Wnt/β-catenin signaling in development and cancer

In damaged kidneys, increased extracellular matrix (ECM) and tissue stiffness stimulate kidney fibrosis through incompletely characterized molecular mechanisms. The transcriptional coactivators yes-associated protein (Yap) and transcriptional coactivator with PDZ-binding motif (Taz) function as mechanosensors in cancer cells and have been implicated in the regulation of myofibroblasts in the kidney. We hypothesized that the development of kidney fibrosis depends on Yap-induced activation and proliferation of kidney fibroblasts. In mice, Yap expression increased in renal fibroblasts after unilateral ureteral obstruction (UUO), in association with worsening of interstitial fibrosis. In cultured fibroblasts, inhibition of Yap/Taz signaling blocked TGF- β 1–induced fibroblast-to-myofibroblast transformation and ECM production, whereas constitutive activation of Yap promoted fibroblast transformation and ECM production even in the absence of TGF- β 1. Moreover, in the absence of TGF- β 1, fibroblasts seeded on a stiffened ECM transformed into myofibroblasts in a process dependent on the activation of Yap. In mice with UUO, the Yap inhibitor verteporfin reduced interstitial fibrosis. Furthermore, Gli1 + cell-specific knockout of Yap/Taz in mice suppressed UUO-induced ECM deposition, myofibroblast accumulation, and interstitial fibrosis. In a UUO-release model, induction of Gli1 + cell-specific Yap/Taz knockout partially reversed the development of interstitial fibrosis. Thus, in th...