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Blocking connexin 43 and its promotion of ATP release from renal tubular epithelial cells ameliorates renal fibrosis
Whether metabolites derived from injured renal tubular epithelial cells (TECs) participate in renal fibrosis is poorly explored. After TEC injury, various metabolites are released and among the most potent is adenosine triphosphate (ATP), which is released via ATP-permeable channels. In these hemich...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9156700/ https://www.ncbi.nlm.nih.gov/pubmed/35641484 http://dx.doi.org/10.1038/s41419-022-04910-w |
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author | Xu, Huzi Wang, Meng Li, Yinzheng Shi, Mengxia Wang, Zheng Cao, Chujin Hong, Yu Hu, Bin Zhu, Han Zhao, Zhi Chu, Xiaoxin Zhu, Fan Deng, Xuan Wu, Jianliang Zhao, Fenfei Guo, Jing Wang, Yuxi Pei, Guangchang Zhu, Fengming Wang, Xiaoyan Yang, Juan Yao, Ying Zeng, Rui |
author_facet | Xu, Huzi Wang, Meng Li, Yinzheng Shi, Mengxia Wang, Zheng Cao, Chujin Hong, Yu Hu, Bin Zhu, Han Zhao, Zhi Chu, Xiaoxin Zhu, Fan Deng, Xuan Wu, Jianliang Zhao, Fenfei Guo, Jing Wang, Yuxi Pei, Guangchang Zhu, Fengming Wang, Xiaoyan Yang, Juan Yao, Ying Zeng, Rui |
author_sort | Xu, Huzi |
collection | PubMed |
description | Whether metabolites derived from injured renal tubular epithelial cells (TECs) participate in renal fibrosis is poorly explored. After TEC injury, various metabolites are released and among the most potent is adenosine triphosphate (ATP), which is released via ATP-permeable channels. In these hemichannels, connexin 43 (Cx43) is the most common member. However, its role in renal interstitial fibrosis (RIF) has not been fully examined. We analyzed renal samples from patients with obstructive nephropathy and mice with unilateral ureteral obstruction (UUO). Cx43-KSP mice were generated to deplete Cx43 in TECs. Through transcriptomics, metabolomics, and single-cell sequencing multi-omics analysis, the relationship among tubular Cx43, ATP, and macrophages in renal fibrosis was explored. The expression of Cx43 in TECs was upregulated in both patients and mice with obstructive nephropathy. Knockdown of Cx43 in TECs or using Cx43-specific inhibitors reduced UUO-induced inflammation and fibrosis in mice. Single-cell RNA sequencing showed that ATP specific receptors, including P2rx4 and P2rx7, were distributed mainly on macrophages. We found that P2rx4- or P2rx7-positive macrophages underwent pyroptosis after UUO, and in vitro ATP directly induced pyroptosis by macrophages. The administration of P2 receptor or P2X7 receptor blockers to UUO mice inhibited macrophage pyroptosis and demonstrated a similar degree of renoprotection as Cx43 genetic depletion. Further, we found that GAP 26 (a Cx43 hemichannel inhibitor) and A-839977 (an inhibitor of the pyroptosis receptor) alleviated UUO-induced fibrosis, while BzATP (the agonist of pyroptosis receptor) exacerbated fibrosis. Single-cell sequencing demonstrated that the pyroptotic macrophages upregulated the release of CXCL10, which activated intrarenal fibroblasts. Cx43 mediates the release of ATP from TECs during renal injury, inducing peritubular macrophage pyroptosis, which subsequently leads to the release of CXCL10 and activation of intrarenal fibroblasts and acceleration of renal fibrosis. |
format | Online Article Text |
id | pubmed-9156700 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-91567002022-06-02 Blocking connexin 43 and its promotion of ATP release from renal tubular epithelial cells ameliorates renal fibrosis Xu, Huzi Wang, Meng Li, Yinzheng Shi, Mengxia Wang, Zheng Cao, Chujin Hong, Yu Hu, Bin Zhu, Han Zhao, Zhi Chu, Xiaoxin Zhu, Fan Deng, Xuan Wu, Jianliang Zhao, Fenfei Guo, Jing Wang, Yuxi Pei, Guangchang Zhu, Fengming Wang, Xiaoyan Yang, Juan Yao, Ying Zeng, Rui Cell Death Dis Article Whether metabolites derived from injured renal tubular epithelial cells (TECs) participate in renal fibrosis is poorly explored. After TEC injury, various metabolites are released and among the most potent is adenosine triphosphate (ATP), which is released via ATP-permeable channels. In these hemichannels, connexin 43 (Cx43) is the most common member. However, its role in renal interstitial fibrosis (RIF) has not been fully examined. We analyzed renal samples from patients with obstructive nephropathy and mice with unilateral ureteral obstruction (UUO). Cx43-KSP mice were generated to deplete Cx43 in TECs. Through transcriptomics, metabolomics, and single-cell sequencing multi-omics analysis, the relationship among tubular Cx43, ATP, and macrophages in renal fibrosis was explored. The expression of Cx43 in TECs was upregulated in both patients and mice with obstructive nephropathy. Knockdown of Cx43 in TECs or using Cx43-specific inhibitors reduced UUO-induced inflammation and fibrosis in mice. Single-cell RNA sequencing showed that ATP specific receptors, including P2rx4 and P2rx7, were distributed mainly on macrophages. We found that P2rx4- or P2rx7-positive macrophages underwent pyroptosis after UUO, and in vitro ATP directly induced pyroptosis by macrophages. The administration of P2 receptor or P2X7 receptor blockers to UUO mice inhibited macrophage pyroptosis and demonstrated a similar degree of renoprotection as Cx43 genetic depletion. Further, we found that GAP 26 (a Cx43 hemichannel inhibitor) and A-839977 (an inhibitor of the pyroptosis receptor) alleviated UUO-induced fibrosis, while BzATP (the agonist of pyroptosis receptor) exacerbated fibrosis. Single-cell sequencing demonstrated that the pyroptotic macrophages upregulated the release of CXCL10, which activated intrarenal fibroblasts. Cx43 mediates the release of ATP from TECs during renal injury, inducing peritubular macrophage pyroptosis, which subsequently leads to the release of CXCL10 and activation of intrarenal fibroblasts and acceleration of renal fibrosis. Nature Publishing Group UK 2022-05-31 /pmc/articles/PMC9156700/ /pubmed/35641484 http://dx.doi.org/10.1038/s41419-022-04910-w Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Xu, Huzi Wang, Meng Li, Yinzheng Shi, Mengxia Wang, Zheng Cao, Chujin Hong, Yu Hu, Bin Zhu, Han Zhao, Zhi Chu, Xiaoxin Zhu, Fan Deng, Xuan Wu, Jianliang Zhao, Fenfei Guo, Jing Wang, Yuxi Pei, Guangchang Zhu, Fengming Wang, Xiaoyan Yang, Juan Yao, Ying Zeng, Rui Blocking connexin 43 and its promotion of ATP release from renal tubular epithelial cells ameliorates renal fibrosis |
title | Blocking connexin 43 and its promotion of ATP release from renal tubular epithelial cells ameliorates renal fibrosis |
title_full | Blocking connexin 43 and its promotion of ATP release from renal tubular epithelial cells ameliorates renal fibrosis |
title_fullStr | Blocking connexin 43 and its promotion of ATP release from renal tubular epithelial cells ameliorates renal fibrosis |
title_full_unstemmed | Blocking connexin 43 and its promotion of ATP release from renal tubular epithelial cells ameliorates renal fibrosis |
title_short | Blocking connexin 43 and its promotion of ATP release from renal tubular epithelial cells ameliorates renal fibrosis |
title_sort | blocking connexin 43 and its promotion of atp release from renal tubular epithelial cells ameliorates renal fibrosis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9156700/ https://www.ncbi.nlm.nih.gov/pubmed/35641484 http://dx.doi.org/10.1038/s41419-022-04910-w |
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