Hyperosmolarity of the renal medulla is essential for urine concentration and water homeostasis. However, how renal medullary collecting duct (MCD) cells survive and function under harsh hyperosmotic stress remains unclear. Using RNA-Seq, we identified SLC38A2 as a novel osmoresponsive neutral amino acid transporter in MCD cells. Hyperosmotic stress-induced cell death in MCD cells occurred mainly via ferroptosis, and it was significantly attenuated by SLC38A2 overexpression but worsened by Slc38a2-gene deletion or silencing. Mechanistic studies revealed that the osmoprotective effect of SLC38A2 is dependent on the activation of mTORC1. Moreover, an in vivo study demonstrated that Slc38a2-knockout mice exhibited significantly increased medullary ferroptosis following water restriction. Collectively, these findings reveal that Slc38a2 is an important osmoresponsive gene in the renal medulla and provide novel insights into the critical role of SLC38A2 in protecting MCD cells from hyperosmolarity-induced ferroptosis via the mTORC1 signalling pathway.
Sequencing data have been deposited in GEO under accession codes GSE206476.All data analysed during this study are included in the manuscript and supporting file; Source Data files have been provided for Figures 1-10 and Figures S1-11.Figure 1 - Source Data 1 and Figure 2 - Source Data 1 contain the numerical data used to generate the figures.
Neutral amino acid transporter SNAT2 protects renal medulla from hypertonicity-induced ferroptosisNCBI Gene Expression Omnibus, GSE206476.
Single-Cell Profiling Reveals Sex, Lineage, and Regional Diversity in the Mouse Kidney.Kidney Cell Explorer.
Genomic Transporter Database - SLC SeriesBioparadigms.
- Xiaoyan Zhang
- Xiaoyan Zhang
- Youfei Guan
- Youfei Guan
- Xiaoyan Zhang
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: The use of animals and the study protocols were reviewed and approved by the Animal Care and Use Review Committee of Dalian Medical University and the study conformed to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (in Guide for the Care and Use of Laboratory Animals, th, Editor. 2011: Washington )
- Mark L Zeidel, Beth Israel Deaconess Medical Center, United States
© 2023, Du et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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