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Loss of DEPTOR in renal tubules protects against cisplatin-induced acute kidney injury

DEP domain containing mTOR-interacting protein (DEPTOR) was originally identified as an in vivo dual inhibitor of mechanistic target of rapamycin (mTOR). It was recently reported to be involved in renal physiology and pathology in vitro; however, its detailed roles and mechanisms in vivo are complet...

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Autores principales: Wang, Caixia, Dai, Huaiqian, Xiong, Zhi, Song, Qiancheng, Zou, Zhipeng, Li, Mangmang, Nie, Jing, Bai, Xiaochun, Chen, Zhenguo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5906659/
https://www.ncbi.nlm.nih.gov/pubmed/29670094
http://dx.doi.org/10.1038/s41419-018-0483-3
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author Wang, Caixia
Dai, Huaiqian
Xiong, Zhi
Song, Qiancheng
Zou, Zhipeng
Li, Mangmang
Nie, Jing
Bai, Xiaochun
Chen, Zhenguo
author_facet Wang, Caixia
Dai, Huaiqian
Xiong, Zhi
Song, Qiancheng
Zou, Zhipeng
Li, Mangmang
Nie, Jing
Bai, Xiaochun
Chen, Zhenguo
author_sort Wang, Caixia
collection PubMed
description DEP domain containing mTOR-interacting protein (DEPTOR) was originally identified as an in vivo dual inhibitor of mechanistic target of rapamycin (mTOR). It was recently reported to be involved in renal physiology and pathology in vitro; however, its detailed roles and mechanisms in vivo are completely unknown. We observed that DEPTOR expression in the kidney was markedly increased on day 3 after cisplatin treatment, at which time cell apoptosis peaked, implicating DEPTOR in cisplatin-induced acute kidney injury (AKI). We then used the Cre–LoxP system to generate mutant mice in which the DEPTOR gene was specifically deleted in the proximal tubule cells. DEPTOR deficiency did not alter the renal histology or functions in the saline-treated group, indicating that DEPTOR is not essential for kidney function under physiological conditions. Interestingly, DEPTOR deletion extensively preserved the renal histology and maintained the kidney functions after cisplatin treatment, suggesting that the absence of DEPTOR ameliorates cisplatin-induced AKI. Mechanistically, DEPTOR modulated p38 MAPK signaling and TNFα production in vivo and in vitro, rather than mTOR signaling, thus moderating the inflammatory response and cell apoptosis induced by cisplatin. Collectively, our findings demonstrate the roles and mechanisms of DEPTOR in the regulation of the renal physiology and pathology, and demonstrate that the loss of DEPTOR in the proximal tubules protects against cisplatin-induced AKI.
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spelling pubmed-59066592018-06-05 Loss of DEPTOR in renal tubules protects against cisplatin-induced acute kidney injury Wang, Caixia Dai, Huaiqian Xiong, Zhi Song, Qiancheng Zou, Zhipeng Li, Mangmang Nie, Jing Bai, Xiaochun Chen, Zhenguo Cell Death Dis Article DEP domain containing mTOR-interacting protein (DEPTOR) was originally identified as an in vivo dual inhibitor of mechanistic target of rapamycin (mTOR). It was recently reported to be involved in renal physiology and pathology in vitro; however, its detailed roles and mechanisms in vivo are completely unknown. We observed that DEPTOR expression in the kidney was markedly increased on day 3 after cisplatin treatment, at which time cell apoptosis peaked, implicating DEPTOR in cisplatin-induced acute kidney injury (AKI). We then used the Cre–LoxP system to generate mutant mice in which the DEPTOR gene was specifically deleted in the proximal tubule cells. DEPTOR deficiency did not alter the renal histology or functions in the saline-treated group, indicating that DEPTOR is not essential for kidney function under physiological conditions. Interestingly, DEPTOR deletion extensively preserved the renal histology and maintained the kidney functions after cisplatin treatment, suggesting that the absence of DEPTOR ameliorates cisplatin-induced AKI. Mechanistically, DEPTOR modulated p38 MAPK signaling and TNFα production in vivo and in vitro, rather than mTOR signaling, thus moderating the inflammatory response and cell apoptosis induced by cisplatin. Collectively, our findings demonstrate the roles and mechanisms of DEPTOR in the regulation of the renal physiology and pathology, and demonstrate that the loss of DEPTOR in the proximal tubules protects against cisplatin-induced AKI. Nature Publishing Group UK 2018-04-18 /pmc/articles/PMC5906659/ /pubmed/29670094 http://dx.doi.org/10.1038/s41419-018-0483-3 Text en © The Author(s) 2018 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/.
spellingShingle Article
Wang, Caixia
Dai, Huaiqian
Xiong, Zhi
Song, Qiancheng
Zou, Zhipeng
Li, Mangmang
Nie, Jing
Bai, Xiaochun
Chen, Zhenguo
Loss of DEPTOR in renal tubules protects against cisplatin-induced acute kidney injury
title Loss of DEPTOR in renal tubules protects against cisplatin-induced acute kidney injury
title_full Loss of DEPTOR in renal tubules protects against cisplatin-induced acute kidney injury
title_fullStr Loss of DEPTOR in renal tubules protects against cisplatin-induced acute kidney injury
title_full_unstemmed Loss of DEPTOR in renal tubules protects against cisplatin-induced acute kidney injury
title_short Loss of DEPTOR in renal tubules protects against cisplatin-induced acute kidney injury
title_sort loss of deptor in renal tubules protects against cisplatin-induced acute kidney injury
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5906659/
https://www.ncbi.nlm.nih.gov/pubmed/29670094
http://dx.doi.org/10.1038/s41419-018-0483-3
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