Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
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
_version_ 1784841161908682752
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
work_keys_str_mv AT guanxu activationofep4alleviatesakitockdtransitionthroughinducingcpt2mediatedlipophagyinrenalmacrophages
AT liuyong activationofep4alleviatesakitockdtransitionthroughinducingcpt2mediatedlipophagyinrenalmacrophages
AT xinwang activationofep4alleviatesakitockdtransitionthroughinducingcpt2mediatedlipophagyinrenalmacrophages
AT qinshaozong activationofep4alleviatesakitockdtransitionthroughinducingcpt2mediatedlipophagyinrenalmacrophages
AT gongshuiqin activationofep4alleviatesakitockdtransitionthroughinducingcpt2mediatedlipophagyinrenalmacrophages
AT xiaotangli activationofep4alleviatesakitockdtransitionthroughinducingcpt2mediatedlipophagyinrenalmacrophages
AT zhangdaohai activationofep4alleviatesakitockdtransitionthroughinducingcpt2mediatedlipophagyinrenalmacrophages
AT liyan activationofep4alleviatesakitockdtransitionthroughinducingcpt2mediatedlipophagyinrenalmacrophages
AT xiongjiachuan activationofep4alleviatesakitockdtransitionthroughinducingcpt2mediatedlipophagyinrenalmacrophages
AT yangke activationofep4alleviatesakitockdtransitionthroughinducingcpt2mediatedlipophagyinrenalmacrophages
AT heting activationofep4alleviatesakitockdtransitionthroughinducingcpt2mediatedlipophagyinrenalmacrophages
AT zhaojinghong activationofep4alleviatesakitockdtransitionthroughinducingcpt2mediatedlipophagyinrenalmacrophages
AT huangyinghui activationofep4alleviatesakitockdtransitionthroughinducingcpt2mediatedlipophagyinrenalmacrophages