Ferroptotic stress promotes the accumulation of pro-inflammatory proximal tubular cells in maladaptive renal repair

  1. Shintaro Ide
  2. Yoshihiko Kobayashi
  3. Kana Ide
  4. Sarah A Strausser
  5. Koki Abe
  6. Savannah Herbek
  7. Lori L O'Brien
  8. Steven D Crowley
  9. Laura Barisoni
  10. Aleksandra Tata
  11. Purushothama Rao Tata
  12. Tomokazu Souma  Is a corresponding author
  1. Duke University School of Medicine, United States
  2. Duke University, United States
  3. University of North Carolina at Chapel Hill, United States

Abstract

Overwhelming lipid peroxidation induces ferroptotic stress and ferroptosis, a non-apoptotic form of regulated cell death that has been implicated in maladaptive renal repair in mice and humans. Using single-cell transcriptomic and mouse genetic approaches, we show that proximal tubular (PT) cells develop a molecularly distinct, pro-inflammatory state following injury. While these inflammatory PT cells transiently appear after mild injury and return to their original state without inducing fibrosis, after severe injury they accumulate and contribute to persistent inflammation. This transient inflammatory PT state significantly downregulates glutathione metabolism genes, making the cells vulnerable to ferroptotic stress. Genetic induction of high ferroptotic stress in these cells after mild injury leads to the accumulation of the inflammatory PT cells, enhancing inflammation and fibrosis. Our study broadens the roles of ferroptotic stress from being a trigger of regulated cell death to include the promotion and accumulation of proinflammatory cells that underlie maladaptive repair.

Data availability

Sequencing data have been deposited in GEO under accession codes GSE161201. Primer sequence information is available in the supplementary file.

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

Article and author information

Author details

  1. Shintaro Ide

    Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9301-211X
  2. Yoshihiko Kobayashi

    Duke University, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Kana Ide

    Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2845-8481
  4. Sarah A Strausser

    Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Koki Abe

    Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Savannah Herbek

    Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Lori L O'Brien

    Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0741-181X
  8. Steven D Crowley

    Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1838-0561
  9. Laura Barisoni

    Department of Pathology, Duke University School of Medicine, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Aleksandra Tata

    Department of Cell Biology, Duke University School of Medicine, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Purushothama Rao Tata

    Duke University, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4837-0337
  12. Tomokazu Souma

    Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, United States
    For correspondence
    tomokazu.souma@duke.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3285-8613

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK123097)

  • Tomokazu Souma

National Institute of Diabetes and Digestive and Kidney Diseases (P30 DK114857)

  • Tomokazu Souma

American Society of Nephrology

  • Tomokazu Souma

American Heart Association

  • Shintaro Ide

Astellas Foundation for Research on Metabolic Disorders

  • Kana Ide

Japan Society for the Promotion of Science

  • Yoshihiko Kobayashi

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

Reviewing Editor

  1. Gregory G Germino, National Institutes of Health, United States

Ethics

Animal experimentation: All animal experiments were approved by the Institutional Animal Care and Use Committee at Duke University and performed according to the IACUC-approved protocol (A051-18-02 and A014-21-01) and adhered to the NIH Guide for the Care and Use of Laboratory.

Version history

  1. Received: March 20, 2021
  2. Preprint posted: March 23, 2021 (view preprint)
  3. Accepted: July 17, 2021
  4. Accepted Manuscript published: July 19, 2021 (version 1)
  5. Version of Record published: July 28, 2021 (version 2)

Copyright

© 2021, Ide 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. Shintaro Ide
  2. Yoshihiko Kobayashi
  3. Kana Ide
  4. Sarah A Strausser
  5. Koki Abe
  6. Savannah Herbek
  7. Lori L O'Brien
  8. Steven D Crowley
  9. Laura Barisoni
  10. Aleksandra Tata
  11. Purushothama Rao Tata
  12. Tomokazu Souma
(2021)
Ferroptotic stress promotes the accumulation of pro-inflammatory proximal tubular cells in maladaptive renal repair
eLife 10:e68603.
https://doi.org/10.7554/eLife.68603

Share this article

https://doi.org/10.7554/eLife.68603

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