Rheb1 protects against cisplatin-induced tubular cell death and acute kidney injury via maintaining mitochondrial homeostasis.

Content Provider	Europe PMC
Author	Lu, Qingmiao Wang, Mingjie Gui, Yuan Hou, Qing Gu, Mengru Liang, Yan Xiao, Bo Zhao, Allan Zijian Dai, Chunsun
Abstract	Ras homolog enriched in brain (Rheb1), a small GTPase, plays a crucial role in regulating cell growth, differentiation, and survival. However, the role and mechanisms for Rheb1 in tubular cell survival and acute kidney injury (AKI) remain unexplored. Here we found that Rheb1 signaling was activated in kidney tubule of AKI patients and cisplatin-treated mice. A mouse model of tubule-specific deletion of Rheb1 (Tubule-Rheb1−/−) was generated. Compared to control littermates, Tubule-Rheb1−/− mice were phenotypically normal within 2 months after birth but developed more severe kidney dysfunction, tubular cell death including apoptosis, necroptosis and ferroptosis, mitochondrial defect and less PGC-1α expression after cisplatin injection. In primary cultured tubular cells, Rheb1 ablation exacerbated cisplatin-induced cell death and mitochondrial defect. Furthermore, haploinsufficiency for Tsc1 in tubular cells led to Rheb1 activation and mitigated cisplatin-induced cell death, mitochondrial defect and AKI. Together, this study uncovers that Rheb1 may protect against cisplatin-induced tubular cell death and AKI through maintaining mitochondrial homeostasis.
Journal	Cell Death & Disease
Volume Number	11
PubMed Central reference number	PMC7221100
Issue Number	5
PubMed reference number	32404875
e-ISSN	20414889
DOI	10.1038/s41419-020-2539-4
Language	English
Publisher	Nature Publishing Group
Publisher Date	2020-05-13
Publisher Place	London
Access Restriction	Open
Rights License	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/. © The Author(s) 2020
Subject Keyword	Cell death Acute kidney injury
Content Type	Text
Resource Type	Article
Subject	Cell Biology Immunology Cellular and Molecular Neuroscience Medicine Cancer Research