Neutral amino acid transporter SLC38A2 protects renal medulla from hyperosmolarity-induced ferroptosis

Abstract

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.

Data availability

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.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Chunxiu Du

    Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, China
    For correspondence
    chunxiu_du@163.com
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4152-4663
  2. Hu Xu

    Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, China
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1198-0932
  3. Cong Cao

    Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Jiahui Cao

    Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Yufei Zhang

    Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, China
    Competing interests
    The authors declare that no competing interests exist.
  6. Cong Zhang

    Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Rongfang Qiao

    Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, China
    Competing interests
    The authors declare that no competing interests exist.
  8. Wenhua Ming

    Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, China
    Competing interests
    The authors declare that no competing interests exist.
  9. Yaqing Li

    Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, China
    Competing interests
    The authors declare that no competing interests exist.
  10. Huiwen Ren

    Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, China
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6037-8561
  11. Xiaohui Cui

    Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, China
    Competing interests
    The authors declare that no competing interests exist.
  12. Zhilin Luan

    Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, China
    Competing interests
    The authors declare that no competing interests exist.
  13. Youfei Guan

    Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, China
    For correspondence
    youfeiguan@163.com
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5231-0209
  14. Xiaoyan Zhang

    Health Science Center, East China Normal University, Shanghai, China
    For correspondence
    xyzhang@hsc.ecnu.edu.cn
    Competing interests
    The authors declare that no competing interests exist.

Funding

National Natural Science Foundation of China (82270703)

  • Xiaoyan Zhang

National Natural Science Foundation of China (81970606)

  • Xiaoyan Zhang

National Natural Science Foundation of China (81970595)

  • Youfei Guan

National Key Research and Development Program of China (2020YFC2005000)

  • Youfei Guan

East China Normal University (2022JKXYD03001)

  • Xiaoyan Zhang

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Mark L Zeidel, Beth Israel Deaconess Medical Center, United States

Ethics

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 )

Version history

  1. Received: May 28, 2022
  2. Accepted: January 31, 2023
  3. Accepted Manuscript published: February 1, 2023 (version 1)
  4. Version of Record published: February 23, 2023 (version 2)

Copyright

© 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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  1. Chunxiu Du
  2. Hu Xu
  3. Cong Cao
  4. Jiahui Cao
  5. Yufei Zhang
  6. Cong Zhang
  7. Rongfang Qiao
  8. Wenhua Ming
  9. Yaqing Li
  10. Huiwen Ren
  11. Xiaohui Cui
  12. Zhilin Luan
  13. Youfei Guan
  14. Xiaoyan Zhang
(2023)
Neutral amino acid transporter SLC38A2 protects renal medulla from hyperosmolarity-induced ferroptosis
eLife 12:e80647.
https://doi.org/10.7554/eLife.80647

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https://doi.org/10.7554/eLife.80647

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