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Enhancer of zeste homolog 2 promotes renal fibrosis after acute kidney injury by inducing epithelial-mesenchymal transition and activation of M2 macrophage polarization
Long-term follow-up data indicates that 1/4 patients with acute kidney injury (AKI) will develop to chronic kidney disease (CKD). Our previous studies have demonstrated that enhancer of zeste homolog 2 (EZH2) played an important role in AKI and CKD. However, the role and mechanisms of EZH2 in AKI-to...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10081989/ https://www.ncbi.nlm.nih.gov/pubmed/37029114 http://dx.doi.org/10.1038/s41419-023-05782-4 |
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author | Zhou, Xun Chen, Hui Hu, Yan Ma, Xiaoyan Li, Jinqing Shi, Yingfeng Tao, Min Wang, Yi Zhong, Qin Yan, Danying Zhuang, Shougang Liu, Na |
author_facet | Zhou, Xun Chen, Hui Hu, Yan Ma, Xiaoyan Li, Jinqing Shi, Yingfeng Tao, Min Wang, Yi Zhong, Qin Yan, Danying Zhuang, Shougang Liu, Na |
author_sort | Zhou, Xun |
collection | PubMed |
description | Long-term follow-up data indicates that 1/4 patients with acute kidney injury (AKI) will develop to chronic kidney disease (CKD). Our previous studies have demonstrated that enhancer of zeste homolog 2 (EZH2) played an important role in AKI and CKD. However, the role and mechanisms of EZH2 in AKI-to-CKD transition are still unclear. Here, we demonstrated EZH2 and H3K27me3 highly upregulated in kidney from patients with ANCA-associated glomerulonephritis, and expressed positively with fibrotic lesion and negatively with renal function. Conditional EZH2 deletion or pharmacological inhibition with 3-DZNeP significantly improved renal function and attenuated pathological lesion in ischemia/reperfusion (I/R) or folic acid (FA) mice models (two models of AKI-to-CKD transition). Mechanistically, we used CUT & Tag technology to verify that EZH2 binding to the PTEN promoter and regulating its transcription, thus regulating its downstream signaling pathways. Genetic or pharmacological depletion of EZH2 upregulated PTEN expression and suppressed the phosphorylation of EGFR and its downstream signaling ERK1/2 and STAT3, consequently alleviating the partial epithelial-mesenchymal transition (EMT), G2/M arrest, and the aberrant secretion of profibrogenic and proinflammatory factors in vivo and vitro experiments. In addition, EZH2 promoted the EMT program induced loss of renal tubular epithelial cell transporters (OAT1, ATPase, and AQP1), and blockade of EZH2 prevented it. We further co-cultured macrophages with the medium of human renal tubular epithelial cells treated with H(2)O(2) and found macrophages transferred to M2 phenotype, and EZH2 could regulate M2 macrophage polarization through STAT6 and PI3K/AKT pathways. These results were further verified in two mice models. Thus, targeted inhibition of EZH2 might be a novel therapy for ameliorating renal fibrosis after acute kidney injury by counteracting partial EMT and blockade of M2 macrophage polarization. |
format | Online Article Text |
id | pubmed-10081989 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-100819892023-04-09 Enhancer of zeste homolog 2 promotes renal fibrosis after acute kidney injury by inducing epithelial-mesenchymal transition and activation of M2 macrophage polarization Zhou, Xun Chen, Hui Hu, Yan Ma, Xiaoyan Li, Jinqing Shi, Yingfeng Tao, Min Wang, Yi Zhong, Qin Yan, Danying Zhuang, Shougang Liu, Na Cell Death Dis Article Long-term follow-up data indicates that 1/4 patients with acute kidney injury (AKI) will develop to chronic kidney disease (CKD). Our previous studies have demonstrated that enhancer of zeste homolog 2 (EZH2) played an important role in AKI and CKD. However, the role and mechanisms of EZH2 in AKI-to-CKD transition are still unclear. Here, we demonstrated EZH2 and H3K27me3 highly upregulated in kidney from patients with ANCA-associated glomerulonephritis, and expressed positively with fibrotic lesion and negatively with renal function. Conditional EZH2 deletion or pharmacological inhibition with 3-DZNeP significantly improved renal function and attenuated pathological lesion in ischemia/reperfusion (I/R) or folic acid (FA) mice models (two models of AKI-to-CKD transition). Mechanistically, we used CUT & Tag technology to verify that EZH2 binding to the PTEN promoter and regulating its transcription, thus regulating its downstream signaling pathways. Genetic or pharmacological depletion of EZH2 upregulated PTEN expression and suppressed the phosphorylation of EGFR and its downstream signaling ERK1/2 and STAT3, consequently alleviating the partial epithelial-mesenchymal transition (EMT), G2/M arrest, and the aberrant secretion of profibrogenic and proinflammatory factors in vivo and vitro experiments. In addition, EZH2 promoted the EMT program induced loss of renal tubular epithelial cell transporters (OAT1, ATPase, and AQP1), and blockade of EZH2 prevented it. We further co-cultured macrophages with the medium of human renal tubular epithelial cells treated with H(2)O(2) and found macrophages transferred to M2 phenotype, and EZH2 could regulate M2 macrophage polarization through STAT6 and PI3K/AKT pathways. These results were further verified in two mice models. Thus, targeted inhibition of EZH2 might be a novel therapy for ameliorating renal fibrosis after acute kidney injury by counteracting partial EMT and blockade of M2 macrophage polarization. Nature Publishing Group UK 2023-04-07 /pmc/articles/PMC10081989/ /pubmed/37029114 http://dx.doi.org/10.1038/s41419-023-05782-4 Text en © The Author(s) 2023 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 Zhou, Xun Chen, Hui Hu, Yan Ma, Xiaoyan Li, Jinqing Shi, Yingfeng Tao, Min Wang, Yi Zhong, Qin Yan, Danying Zhuang, Shougang Liu, Na Enhancer of zeste homolog 2 promotes renal fibrosis after acute kidney injury by inducing epithelial-mesenchymal transition and activation of M2 macrophage polarization |
title | Enhancer of zeste homolog 2 promotes renal fibrosis after acute kidney injury by inducing epithelial-mesenchymal transition and activation of M2 macrophage polarization |
title_full | Enhancer of zeste homolog 2 promotes renal fibrosis after acute kidney injury by inducing epithelial-mesenchymal transition and activation of M2 macrophage polarization |
title_fullStr | Enhancer of zeste homolog 2 promotes renal fibrosis after acute kidney injury by inducing epithelial-mesenchymal transition and activation of M2 macrophage polarization |
title_full_unstemmed | Enhancer of zeste homolog 2 promotes renal fibrosis after acute kidney injury by inducing epithelial-mesenchymal transition and activation of M2 macrophage polarization |
title_short | Enhancer of zeste homolog 2 promotes renal fibrosis after acute kidney injury by inducing epithelial-mesenchymal transition and activation of M2 macrophage polarization |
title_sort | enhancer of zeste homolog 2 promotes renal fibrosis after acute kidney injury by inducing epithelial-mesenchymal transition and activation of m2 macrophage polarization |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10081989/ https://www.ncbi.nlm.nih.gov/pubmed/37029114 http://dx.doi.org/10.1038/s41419-023-05782-4 |
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