肌成纤维细胞
纤维化
细胞外基质
成纤维细胞
医学
胶质1
癌症研究
转化生长因子
生物
化学
细胞生物学
病理
信号转导
细胞培养
刺猬信号通路
遗传学
作者
Liang Ming,Michael Yu,Ruohan Xia,Ke Song,Jun Wang,Jinlong Luo,Guang Chen,Jizhong Cheng
出处
期刊:Journal of The American Society of Nephrology
日期:2017-08-02
卷期号:28 (11): 3278-3290
被引量:113
标识
DOI:10.1681/asn.2015121354
摘要
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 the kidney, Yap is a tissue mechanosensor that can be activated by ECM and transforms fibroblasts into myofibroblasts; the interaction of Yap/Taz and ECM forms a feed-forward loop resulting in kidney fibrosis. Identifying mechanisms that interrupt this profibrotic cycle could lead to the development of anti-fibrosis therapy.
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