Yap/Taz Deletion in Gli+ Cell-Derived Myofibroblasts Attenuates Fibrosis
Yap/Taz Deletion in Gli+ Cell-Derived Myofibroblasts Attenuates Fibrosis
复制标题
DOI：
10.1681/asn.2015121354
复制
发表时间：
2017-11-01
影响因子：
13.6
通讯作者：
Cheng, Jizhong
中科院分区：
文献类型：
--
作者：
Liang, Ming;Yu, Michael;Cheng, Jizhong
在受损的肾脏中，细胞外基质（ECM）和组织硬度增加通过不完全表征的分子机制刺激肾脏纤维化。转录辅激活因子yes相关蛋白（雅普）和具有PDZ结合基序的转录辅激活因子（Taz）在癌细胞中起机械传感器的作用，并参与肾脏中肌成纤维细胞的调节。我们假设肾纤维化的发展依赖于Yap诱导的肾成纤维细胞的活化和增殖。在小鼠中，单侧输尿管梗阻（UUO）后肾成纤维细胞中雅普表达增加，与间质纤维化恶化相关。在培养的成纤维细胞中，抑制雅普/Taz信号传导阻断了TGF-β 1诱导的成纤维细胞向肌成纤维细胞的转化和ECM的产生，而组成型激活雅普促进成纤维细胞转化和ECM的产生，即使在没有TGF-β 1的情况下。此外，在缺乏TGF-β 1的情况下，接种在硬化ECM上的成纤维细胞在依赖于雅普活化的过程中转化为肌成纤维细胞。在患有UUO的小鼠中，雅普抑制剂维替泊芬减少了间质纤维化。此外，GUY细胞特异性敲除小鼠中的雅普/Taz抑制UUO诱导的ECM沉积、肌成纤维细胞积聚和间质纤维化。在UUO释放模型中，诱导Gli 1（+）细胞特异性雅普/Taz敲除部分逆转了间质纤维化的发展。因此，在肾脏中，雅普是一种组织力学传感器，可被ECM激活并将成纤维细胞转化为肌成纤维细胞;雅普/Taz和ECM的相互作用形成前馈回路，导致肾脏纤维化。确定中断这种促纤维化周期的机制可能会导致抗纤维化治疗的发展。
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-beta 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-beta 1. Moreover, in the absence of TGF-beta 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, GUY' 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.