YAP/Smad3 promotes pathological extracellular matrix microenviroment-induced bladder smooth muscle proliferation in bladder fibrosis progression.
YAP/Smad3 promotes pathological extracellular matrix microenviroment-induced bladder smooth muscle proliferation in bladder fibrosis progression.
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YAP/Smad3 在膀胱纤维化进展中促进病理性细胞外基质微环境诱导的膀胱平滑肌增殖
作者：
Di, Xing-Peng;Jin, Xi;Ai, Jian-Zhong;Xiang, Li-Yuan;Gao, Xiao-Shuai;Xiao, Kai-Wen;Li, Hong;Luo, DeYi;Wang, Kun-Jie
摘要纤维化是一种细胞外基质（ECM）过度沉积的慢性炎症过程，是不可逆的。患者患有由膀胱纤维化引起的膀胱功能障碍。此外，ECM与膀胱纤维化之间的相互作用机制仍不清楚。因此，我们评估了Yes相关蛋白（雅普）在纤维化过程中对膀胱平滑肌增殖的关键作用。我们发现刚性ECM增加了人膀胱平滑肌细胞（hBdSMC）核内雅普的表达和移位。序列分析和蛋白质组学研究表明，雅普与Smad 3结合，通过MAPK/ERK信号通路促进hBdSMC在刚性ECM中的增殖。此外，CUT和TAG测序以及双荧光素酶测定证明Smad 3抑制JUN的转录。在部分膀胱出口梗阻（pBOO）大鼠模型中使用雅普抑制剂CA 3。结果表明，CA 3抑制膀胱平滑肌增殖。总之，雅普与Smad 3在细胞核内的结合抑制了JUN的转录，并通过MAPK/ERK信号通路促进了膀胱平滑肌的增殖。本研究确定了机械力诱导膀胱纤维化的新机制，为雅普相关器官纤维化提供了见解。
Abstract Fibrosis is a chronic inflammation process with excess extracellular matrix (ECM) deposition that cannot be reversed. Patients suffer from bladder dysfunction caused by bladder fibrosis. Moreover, the interactive mechanisms between ECM and bladder fibrosis are still obscure. Hence, we assessed the pivotal effect of Yes‐associated protein (YAP) on the proliferation of bladder smooth muscle in fibrosis process. We identified that stiff ECM increased the expression and translocation of YAP in the nucleus of human bladder smooth muscle cell (hBdSMC). Sequencings and proteomics revealed that YAP bound to Smad3 and promoted the proliferation of hBdSMC via MAPK/ERK signaling pathway in stiff ECM. Moreover, CUT and TAG sequencing and dual‐luciferase assays demonstrated that Smad3 inhibited the transcription of JUN. The YAP inhibitor CA3 was used in a partial bladder outlet obstruction (pBOO) rat model. The results showed that CA3 attenuated bladder smooth muscle proliferation. Collectively, YAP binding with Smad3 in the nucleus inhibited the transcription of JUN, and promoted the proliferation of bladder smooth muscle through the MAPK/ERK signaling pathway. The current study identified a novel mechanism of mechanical force induced bladder fibrosis that provided insights in YAP‐associated organ fibrosis.
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