Mechanosensitive Piezo1 channels mediate renal fibrosis
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,...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2022-04-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.152330 |
| _version_ | 1811237993715859456 |
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| author | Xiaoduo Zhao Yonglun Kong Baien Liang Jinhai Xu Yu Lin Nan Zhou Jing Li Bin Jiang Jianding Cheng Chunling Li Weidong Wang |
| author_facet | Xiaoduo Zhao Yonglun Kong Baien Liang Jinhai Xu Yu Lin Nan Zhou Jing Li Bin Jiang Jianding Cheng Chunling Li Weidong Wang |
| author_sort | Xiaoduo Zhao |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T12:34:01Z |
| format | Article |
| id | doaj.art-537f7b8bb1be44fea92580272e17daae |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-04-12T12:34:01Z |
| publishDate | 2022-04-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-537f7b8bb1be44fea92580272e17daae2022-12-22T03:32:57ZengAmerican Society for Clinical investigationJCI Insight2379-37082022-04-0177Mechanosensitive Piezo1 channels mediate renal fibrosisXiaoduo ZhaoYonglun KongBaien LiangJinhai XuYu LinNan ZhouJing LiBin JiangJianding ChengChunling LiWeidong WangKidney 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.https://doi.org/10.1172/jci.insight.152330Nephrology |
| spellingShingle | Xiaoduo Zhao Yonglun Kong Baien Liang Jinhai Xu Yu Lin Nan Zhou Jing Li Bin Jiang Jianding Cheng Chunling Li Weidong Wang Mechanosensitive Piezo1 channels mediate renal fibrosis JCI Insight Nephrology |
| title | Mechanosensitive Piezo1 channels mediate renal fibrosis |
| title_full | Mechanosensitive Piezo1 channels mediate renal fibrosis |
| title_fullStr | Mechanosensitive Piezo1 channels mediate renal fibrosis |
| title_full_unstemmed | Mechanosensitive Piezo1 channels mediate renal fibrosis |
| title_short | Mechanosensitive Piezo1 channels mediate renal fibrosis |
| title_sort | mechanosensitive piezo1 channels mediate renal fibrosis |
| topic | Nephrology |
| url | https://doi.org/10.1172/jci.insight.152330 |
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