Mechanosensitive Piezo1 channels mediate renal fibrosis.
Mechanosensitive Piezo1 channels mediate renal fibrosis.
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机械敏感 Piezo1 通道介导肾纤维化
DOI：
10.1172/jci.insight.152330
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发表时间：
2022-04-08
期刊：
影响因子：
8
通讯作者：
Wang, Weidong
中科院分区：
文献类型：
--
作者：
Zhao, Xiaoduo;Kong, Yonglun;Liang, Baien;Xu, Jinhai;Lin, Yu;Zhou, Nan;Li, Jing;Jiang, Bin;Cheng, Jianding;Li, Chunling;Wang, Weidong
肾纤维化是进行性肾脏疾病的最终共同途径，其潜在机制尚未完全了解。本研究的目的是探讨Piezo 1（一种机械敏感性非选择性阳离子通道）在肾纤维化中的作用。在人纤维化肾脏中，Piezo 1蛋白表达显著上调。单侧输尿管梗阻（UUO）或叶酸治疗的小鼠肾脏中Piezo 1蛋白的丰度显著增加。用非特异性抑制剂GsMTx 4抑制Piezo 1可显著改善UUO或叶酸诱导的肾纤维化。机械拉伸，压缩，或刚度诱导的Piezo 1激活和促纤维化反应，在人类HK 2细胞和原代培养的小鼠近端肾小管细胞（mPTC），这是大大防止抑制或沉默的Piezo 1。TGF-β1诱导HK 2细胞和mPTC中Piezo 1表达增加和促纤维化表型改变，这再次被Piezo 1抑制显著阻止。通过Piezo 1激动剂Yoda 1激活Piezo 1，引起HK 2细胞中的钙内流和促纤维化反应，并诱导钙依赖性蛋白酶calpain 2激活，随后粘附复合物蛋白talin 1切割和整合素β1上调。此外，Yoda 1促进ECM和整合素β1之间的联系。结论：Piezo 1可能通过激活钙/钙蛋白酶2/整合素β1通路参与肾纤维化的进展和近端肾小管细胞的促纤维化改变。
Kidney fibrosis is the final common pathway of progressive kidney diseases, the underlying mechanisms of which are not fully understood. The purpose of the current study is to investigate a role of Piezo1, a mechanosensitive nonselective cation channel, in kidney fibrosis. In human fibrotic kidneys, Piezo1 protein expression was markedly upregulated. The abundance of Piezo1 protein in kidneys of mice with unilateral ureter obstruction (UUO) or with folic acid treatment was significantly increased. Inhibition of Piezo1 with nonspecific inhibitor GsMTx4 markedly ameliorated UUO- or folic acid–induced kidney fibrosis. Mechanical stretch, compression, or stiffness induced Piezo1 activation and profibrotic responses in human HK2 cells and primary cultured mouse proximal tubular cells (mPTCs), which were greatly prevented by inhibition or silence of Piezo1. TGF-β1 induced increased Piezo1 expression and profibrotic phenotypic alterations in HK2 cells and mPTCs, which were again markedly prevented by inhibition of Piezo1. Activation of Piezo1 by Yoda1, a Piezo1 agonist, caused calcium influx and profibrotic responses in HK2 cells and induced calcium-dependent protease calpain2 activation, followed by adhesion complex protein talin1 cleavage and upregulation of integrin β1. Also, Yoda1 promoted the link between ECM and integrin β1. In conclusion, Piezo1 is involved in the progression of kidney fibrosis and profibrotic alterations in renal proximal tubular cells, likely through activating calcium/calpain2/integrin β1 pathway.
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影响因子：
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