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The down-regulation of XBP1, an unfolded protein response effector, promotes acute kidney injury to chronic kidney disease transition

BACKGROUND: The activation of the unfolded protein response (UPR) is closely linked to the pathogenesis of renal injuries. However, the role of XBP1, a crucial regulator of adaptive UPR, remains unclear during the transition from acute kidney injury (AKI) to chronic kidney disease (CKD). METHODS: We...

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Autores principales: Chen, Jia-Huang, Wu, Chia-Hsien, Jheng, Jia-Rong, Chao, Chia-Ter, Huang, Jenq-Wen, Hung, Kuan-Yu, Liu, Shing-Hwa, Chiang, Chih-Kang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9241279/
https://www.ncbi.nlm.nih.gov/pubmed/35765067
http://dx.doi.org/10.1186/s12929-022-00828-9
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author Chen, Jia-Huang
Wu, Chia-Hsien
Jheng, Jia-Rong
Chao, Chia-Ter
Huang, Jenq-Wen
Hung, Kuan-Yu
Liu, Shing-Hwa
Chiang, Chih-Kang
author_facet Chen, Jia-Huang
Wu, Chia-Hsien
Jheng, Jia-Rong
Chao, Chia-Ter
Huang, Jenq-Wen
Hung, Kuan-Yu
Liu, Shing-Hwa
Chiang, Chih-Kang
author_sort Chen, Jia-Huang
collection PubMed
description BACKGROUND: The activation of the unfolded protein response (UPR) is closely linked to the pathogenesis of renal injuries. However, the role of XBP1, a crucial regulator of adaptive UPR, remains unclear during the transition from acute kidney injury (AKI) to chronic kidney disease (CKD). METHODS: We characterized XBP1 expressions in different mouse models of kidney injuries, including unilateral ischemia–reperfusion injury (UIRI), unilateral ureteral obstruction, and adenine-induced CKD, followed by generating proximal tubular XBP1 conditional knockout (XBP1(cKO)) mice for examining the influences of XBP1. Human proximal tubular epithelial cells (HK-2) were silenced of XBP1 to conduct proteomic analysis and investigate the underlying mechanism. RESULTS: We showed a tripartite activation of UPR in injured kidneys. XBP1 expressions were attenuated after AKI and inversely correlated with the severity of post-AKI renal fibrosis. XBP1(cKO) mice exhibited more severe renal fibrosis in the UIRI model than wide-type littermates. Silencing XBP1 induced HK-2 cell cycle arrest in G2M phase, inhibited cell proliferation, and promoted TGF-β1 secretion. Proteomic analysis identified TNF receptor associated protein 1 (Trap1) as the potential downstream target transcriptionally regulated by XBP1s. Trap1 overexpression can alleviate silencing XBP1 induced profibrotic factor expressions and cell cycle arrest. CONCLUSION: The loss of XBP1 in kidney injury was profibrotic, and the process was mediated by autocrine and paracrine regulations in combination. The present study identified the XBP1-Trap1 axis as an instrumental mechanism responsible for post-AKI fibrosis, which is a novel regulatory pathway. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12929-022-00828-9.
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spelling pubmed-92412792022-06-30 The down-regulation of XBP1, an unfolded protein response effector, promotes acute kidney injury to chronic kidney disease transition Chen, Jia-Huang Wu, Chia-Hsien Jheng, Jia-Rong Chao, Chia-Ter Huang, Jenq-Wen Hung, Kuan-Yu Liu, Shing-Hwa Chiang, Chih-Kang J Biomed Sci Research BACKGROUND: The activation of the unfolded protein response (UPR) is closely linked to the pathogenesis of renal injuries. However, the role of XBP1, a crucial regulator of adaptive UPR, remains unclear during the transition from acute kidney injury (AKI) to chronic kidney disease (CKD). METHODS: We characterized XBP1 expressions in different mouse models of kidney injuries, including unilateral ischemia–reperfusion injury (UIRI), unilateral ureteral obstruction, and adenine-induced CKD, followed by generating proximal tubular XBP1 conditional knockout (XBP1(cKO)) mice for examining the influences of XBP1. Human proximal tubular epithelial cells (HK-2) were silenced of XBP1 to conduct proteomic analysis and investigate the underlying mechanism. RESULTS: We showed a tripartite activation of UPR in injured kidneys. XBP1 expressions were attenuated after AKI and inversely correlated with the severity of post-AKI renal fibrosis. XBP1(cKO) mice exhibited more severe renal fibrosis in the UIRI model than wide-type littermates. Silencing XBP1 induced HK-2 cell cycle arrest in G2M phase, inhibited cell proliferation, and promoted TGF-β1 secretion. Proteomic analysis identified TNF receptor associated protein 1 (Trap1) as the potential downstream target transcriptionally regulated by XBP1s. Trap1 overexpression can alleviate silencing XBP1 induced profibrotic factor expressions and cell cycle arrest. CONCLUSION: The loss of XBP1 in kidney injury was profibrotic, and the process was mediated by autocrine and paracrine regulations in combination. The present study identified the XBP1-Trap1 axis as an instrumental mechanism responsible for post-AKI fibrosis, which is a novel regulatory pathway. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12929-022-00828-9. BioMed Central 2022-06-28 /pmc/articles/PMC9241279/ /pubmed/35765067 http://dx.doi.org/10.1186/s12929-022-00828-9 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Chen, Jia-Huang
Wu, Chia-Hsien
Jheng, Jia-Rong
Chao, Chia-Ter
Huang, Jenq-Wen
Hung, Kuan-Yu
Liu, Shing-Hwa
Chiang, Chih-Kang
The down-regulation of XBP1, an unfolded protein response effector, promotes acute kidney injury to chronic kidney disease transition
title The down-regulation of XBP1, an unfolded protein response effector, promotes acute kidney injury to chronic kidney disease transition
title_full The down-regulation of XBP1, an unfolded protein response effector, promotes acute kidney injury to chronic kidney disease transition
title_fullStr The down-regulation of XBP1, an unfolded protein response effector, promotes acute kidney injury to chronic kidney disease transition
title_full_unstemmed The down-regulation of XBP1, an unfolded protein response effector, promotes acute kidney injury to chronic kidney disease transition
title_short The down-regulation of XBP1, an unfolded protein response effector, promotes acute kidney injury to chronic kidney disease transition
title_sort down-regulation of xbp1, an unfolded protein response effector, promotes acute kidney injury to chronic kidney disease transition
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9241279/
https://www.ncbi.nlm.nih.gov/pubmed/35765067
http://dx.doi.org/10.1186/s12929-022-00828-9
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