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Activation of EP4 alleviates AKI-to-CKD transition through inducing CPT2-mediated lipophagy in renal macrophages
Acute kidney injury (AKI) is a common clinical syndrome with complex pathogenesis, characterized by a rapid decline in kidney function in the short term. Worse still, the incomplete recovery from AKI increases the risk of progression to chronic kidney disease (CKD). However, the pathogenesis and und...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9709464/ https://www.ncbi.nlm.nih.gov/pubmed/36467025 http://dx.doi.org/10.3389/fphar.2022.1030800 |
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author | Guan, Xu Liu, Yong Xin, Wang Qin, Shaozong Gong, Shuiqin Xiao, Tangli Zhang, Daohai Li, Yan Xiong, Jiachuan Yang, Ke He, Ting Zhao, Jinghong Huang, Yinghui |
author_facet | Guan, Xu Liu, Yong Xin, Wang Qin, Shaozong Gong, Shuiqin Xiao, Tangli Zhang, Daohai Li, Yan Xiong, Jiachuan Yang, Ke He, Ting Zhao, Jinghong Huang, Yinghui |
author_sort | Guan, Xu |
collection | PubMed |
description | Acute kidney injury (AKI) is a common clinical syndrome with complex pathogenesis, characterized by a rapid decline in kidney function in the short term. Worse still, the incomplete recovery from AKI increases the risk of progression to chronic kidney disease (CKD). However, the pathogenesis and underlying mechanism remain largely unknown. Macrophages play an important role during kidney injury and tissue repair, but its role in AKI-to-CKD transition remains elusive. Herein, single nucleus RNA sequencing (snRNA-Seq) and flow cytometry validations showed that E-type prostaglandin receptor 4 (EP4) was selectively activated in renal macrophages, rather than proximal tubules, in ischemia-reperfusion injury (IRI)-induced AKI-to-CKD transition mouse model. EP4 inhibition aggravated AKI-to-CKD transition, while EP4 activation impeded the progression of AKI to CKD though regulating macrophage polarization. Mechanistically, network pharmacological analysis and subsequent experimental verifications revealed that the activated EP4 inhibited macrophage polarization through inducing Carnitine palmitoyltransferase 2 (CPT2)-mediated lipophagy in macrophages. Further, CPT2 inhibition abrogated the protective effect of EP4 on AKI-to-CKD transition. Taken together, our findings demonstrate that EP4-CPT2 signaling-mediated lipophagy in macrophages plays a pivotal role in the transition of AKI to CKD and targeting EP4-CPT2 axis could serve as a promising therapeutic approach for retarding AKI and its progression to CKD. |
format | Online Article Text |
id | pubmed-9709464 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-97094642022-12-01 Activation of EP4 alleviates AKI-to-CKD transition through inducing CPT2-mediated lipophagy in renal macrophages Guan, Xu Liu, Yong Xin, Wang Qin, Shaozong Gong, Shuiqin Xiao, Tangli Zhang, Daohai Li, Yan Xiong, Jiachuan Yang, Ke He, Ting Zhao, Jinghong Huang, Yinghui Front Pharmacol Pharmacology Acute kidney injury (AKI) is a common clinical syndrome with complex pathogenesis, characterized by a rapid decline in kidney function in the short term. Worse still, the incomplete recovery from AKI increases the risk of progression to chronic kidney disease (CKD). However, the pathogenesis and underlying mechanism remain largely unknown. Macrophages play an important role during kidney injury and tissue repair, but its role in AKI-to-CKD transition remains elusive. Herein, single nucleus RNA sequencing (snRNA-Seq) and flow cytometry validations showed that E-type prostaglandin receptor 4 (EP4) was selectively activated in renal macrophages, rather than proximal tubules, in ischemia-reperfusion injury (IRI)-induced AKI-to-CKD transition mouse model. EP4 inhibition aggravated AKI-to-CKD transition, while EP4 activation impeded the progression of AKI to CKD though regulating macrophage polarization. Mechanistically, network pharmacological analysis and subsequent experimental verifications revealed that the activated EP4 inhibited macrophage polarization through inducing Carnitine palmitoyltransferase 2 (CPT2)-mediated lipophagy in macrophages. Further, CPT2 inhibition abrogated the protective effect of EP4 on AKI-to-CKD transition. Taken together, our findings demonstrate that EP4-CPT2 signaling-mediated lipophagy in macrophages plays a pivotal role in the transition of AKI to CKD and targeting EP4-CPT2 axis could serve as a promising therapeutic approach for retarding AKI and its progression to CKD. Frontiers Media S.A. 2022-11-16 /pmc/articles/PMC9709464/ /pubmed/36467025 http://dx.doi.org/10.3389/fphar.2022.1030800 Text en Copyright © 2022 Guan, Liu, Xin, Qin, Gong, Xiao, Zhang, Li, Xiong, Yang, He, Zhao and Huang. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Pharmacology Guan, Xu Liu, Yong Xin, Wang Qin, Shaozong Gong, Shuiqin Xiao, Tangli Zhang, Daohai Li, Yan Xiong, Jiachuan Yang, Ke He, Ting Zhao, Jinghong Huang, Yinghui Activation of EP4 alleviates AKI-to-CKD transition through inducing CPT2-mediated lipophagy in renal macrophages |
title | Activation of EP4 alleviates AKI-to-CKD transition through inducing CPT2-mediated lipophagy in renal macrophages |
title_full | Activation of EP4 alleviates AKI-to-CKD transition through inducing CPT2-mediated lipophagy in renal macrophages |
title_fullStr | Activation of EP4 alleviates AKI-to-CKD transition through inducing CPT2-mediated lipophagy in renal macrophages |
title_full_unstemmed | Activation of EP4 alleviates AKI-to-CKD transition through inducing CPT2-mediated lipophagy in renal macrophages |
title_short | Activation of EP4 alleviates AKI-to-CKD transition through inducing CPT2-mediated lipophagy in renal macrophages |
title_sort | activation of ep4 alleviates aki-to-ckd transition through inducing cpt2-mediated lipophagy in renal macrophages |
topic | Pharmacology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9709464/ https://www.ncbi.nlm.nih.gov/pubmed/36467025 http://dx.doi.org/10.3389/fphar.2022.1030800 |
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