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Farnesoid X receptor promotes renal ischaemia‐reperfusion injury by inducing tubular epithelial cell apoptosis

PURPOSE: We investigated the role of farnesoid X receptor (FXR), a ligand‐dependent transcription factor, in renal ischaemia‐reperfusion (I/R) injury. MATERIALS AND METHODS: We performed unilateral renal I/R model in FXR knockout (Fxr(−/−)) and wild‐type (WT) mice in vivo and a hypoxia‐reoxygenation...

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Autores principales: Xu, Yao, Li, Dawei, Wu, Jiajin, Zhang, Minfang, Shao, Xinghua, Xu, Longmei, Tang, Lumin, Zhu, Minyan, Ni, Zhaohui, Zhang, Ming, Mou, Shan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016637/
https://www.ncbi.nlm.nih.gov/pubmed/33594777
http://dx.doi.org/10.1111/cpr.13005
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author Xu, Yao
Li, Dawei
Wu, Jiajin
Zhang, Minfang
Shao, Xinghua
Xu, Longmei
Tang, Lumin
Zhu, Minyan
Ni, Zhaohui
Zhang, Ming
Mou, Shan
author_facet Xu, Yao
Li, Dawei
Wu, Jiajin
Zhang, Minfang
Shao, Xinghua
Xu, Longmei
Tang, Lumin
Zhu, Minyan
Ni, Zhaohui
Zhang, Ming
Mou, Shan
author_sort Xu, Yao
collection PubMed
description PURPOSE: We investigated the role of farnesoid X receptor (FXR), a ligand‐dependent transcription factor, in renal ischaemia‐reperfusion (I/R) injury. MATERIALS AND METHODS: We performed unilateral renal I/R model in FXR knockout (Fxr(−/−)) and wild‐type (WT) mice in vivo and a hypoxia‐reoxygenation (H/R) model in vitro. The pathways by which FXR induces apoptosis were detected using a proteome profiler array. The effects of FXR on apoptosis were evaluated using immunoblotting, TUNEL assays and flow cytometry. RESULTS: Compared with WT mice, Fxr(−/−) mice showed improved renal function and reduced tubular injury scores and apoptosis. Consistent with the in vivo results, the silencing of FXR decreased the number of apoptotic HK‐2 cells after H/R, while FXR overexpression aggravated apoptosis. Notably, bone marrow transplantation (BMT) and immunohistochemistry experiments revealed the involvement of FXR in the tubular epithelium rather than in inflammatory cells. Furthermore, in vivo and in vitro studies demonstrated that FXR deficiency increased phosphorylated Bcl‐2 agonist of cell death (p‐Bad) expression levels and the ratio of Bcl‐2/Bcl‐xL to Bax expression in the kidney. Treatment with wortmannin, which reduced p‐Bad expression, inhibited the effects of FXR deficiency and eliminated the tolerance of Fxr(−/−) mouse kidneys to I/R injury. CONCLUSIONS: These results established the pivotal importance of FXR inactivation in tubular epithelial cells after I/R injury. FXR may promote the apoptosis of renal tubular epithelial cells by inhibiting PI3k/Akt‐mediated Bad phosphorylation to cause renal I/R damage.
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spelling pubmed-80166372021-04-02 Farnesoid X receptor promotes renal ischaemia‐reperfusion injury by inducing tubular epithelial cell apoptosis Xu, Yao Li, Dawei Wu, Jiajin Zhang, Minfang Shao, Xinghua Xu, Longmei Tang, Lumin Zhu, Minyan Ni, Zhaohui Zhang, Ming Mou, Shan Cell Prolif Original Articles PURPOSE: We investigated the role of farnesoid X receptor (FXR), a ligand‐dependent transcription factor, in renal ischaemia‐reperfusion (I/R) injury. MATERIALS AND METHODS: We performed unilateral renal I/R model in FXR knockout (Fxr(−/−)) and wild‐type (WT) mice in vivo and a hypoxia‐reoxygenation (H/R) model in vitro. The pathways by which FXR induces apoptosis were detected using a proteome profiler array. The effects of FXR on apoptosis were evaluated using immunoblotting, TUNEL assays and flow cytometry. RESULTS: Compared with WT mice, Fxr(−/−) mice showed improved renal function and reduced tubular injury scores and apoptosis. Consistent with the in vivo results, the silencing of FXR decreased the number of apoptotic HK‐2 cells after H/R, while FXR overexpression aggravated apoptosis. Notably, bone marrow transplantation (BMT) and immunohistochemistry experiments revealed the involvement of FXR in the tubular epithelium rather than in inflammatory cells. Furthermore, in vivo and in vitro studies demonstrated that FXR deficiency increased phosphorylated Bcl‐2 agonist of cell death (p‐Bad) expression levels and the ratio of Bcl‐2/Bcl‐xL to Bax expression in the kidney. Treatment with wortmannin, which reduced p‐Bad expression, inhibited the effects of FXR deficiency and eliminated the tolerance of Fxr(−/−) mouse kidneys to I/R injury. CONCLUSIONS: These results established the pivotal importance of FXR inactivation in tubular epithelial cells after I/R injury. FXR may promote the apoptosis of renal tubular epithelial cells by inhibiting PI3k/Akt‐mediated Bad phosphorylation to cause renal I/R damage. John Wiley and Sons Inc. 2021-02-16 /pmc/articles/PMC8016637/ /pubmed/33594777 http://dx.doi.org/10.1111/cpr.13005 Text en © 2021 The Authors. Cell Proliferation Published by John Wiley & Sons Ltd. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Xu, Yao
Li, Dawei
Wu, Jiajin
Zhang, Minfang
Shao, Xinghua
Xu, Longmei
Tang, Lumin
Zhu, Minyan
Ni, Zhaohui
Zhang, Ming
Mou, Shan
Farnesoid X receptor promotes renal ischaemia‐reperfusion injury by inducing tubular epithelial cell apoptosis
title Farnesoid X receptor promotes renal ischaemia‐reperfusion injury by inducing tubular epithelial cell apoptosis
title_full Farnesoid X receptor promotes renal ischaemia‐reperfusion injury by inducing tubular epithelial cell apoptosis
title_fullStr Farnesoid X receptor promotes renal ischaemia‐reperfusion injury by inducing tubular epithelial cell apoptosis
title_full_unstemmed Farnesoid X receptor promotes renal ischaemia‐reperfusion injury by inducing tubular epithelial cell apoptosis
title_short Farnesoid X receptor promotes renal ischaemia‐reperfusion injury by inducing tubular epithelial cell apoptosis
title_sort farnesoid x receptor promotes renal ischaemia‐reperfusion injury by inducing tubular epithelial cell apoptosis
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016637/
https://www.ncbi.nlm.nih.gov/pubmed/33594777
http://dx.doi.org/10.1111/cpr.13005
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