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.

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.

Reviewing Editor

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

Publication 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.

Metrics

  • 2,890
    Page views
  • 565
    Downloads
  • 21
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Further reading

    1. Cell Biology
    2. Immunology and Inflammation
    Ana J Caetano, Yushi Redhead ... Paul T Sharpe
    Research Article Updated

    The interplay among different cells in a tissue is essential for maintaining homeostasis. Although disease states have been traditionally attributed to individual cell types, increasing evidence and new therapeutic options have demonstrated the primary role of multicellular functions to understand health and disease, opening new avenues to understand pathogenesis and develop new treatment strategies. We recently described the cellular composition and dynamics of the human oral mucosa; however, the spatial arrangement of cells is needed to better understand a morphologically complex tissue. Here, we link single-cell RNA sequencing, spatial transcriptomics, and high-resolution multiplex fluorescence in situ hybridisation to characterise human oral mucosa in health and oral chronic inflammatory disease. We deconvolved expression for resolution enhancement of spatial transcriptomic data and defined highly specialised epithelial and stromal compartments describing location-specific immune programs. Furthermore, we spatially mapped a rare pathogenic fibroblast population localised in a highly immunogenic region, responsible for lymphocyte recruitment through CXCL8 and CXCL10 and with a possible role in pathological angiogenesis through ALOX5AP. Collectively, our study provides a comprehensive reference for the study of oral chronic disease pathogenesis.

    1. Cell Biology
    2. Developmental Biology
    Eunjin Cho, Xiangguo Che ... Tae-Hoon Lee
    Research Article

    Peroxiredoxin 5 (Prdx5) is involved in pathophysiological regulation via the stress-induced cellular response. However, its function in the bone remains largely unknown. Here, we show that Prdx5 is involved in osteoclast and osteoblast differentiation, resulting in osteoporotic phenotypes in Prdx5 knockout (Prdx5Ko) male mice. To investigate the function of Prdx5 in the bone, osteoblasts were analyzed through immunoprecipitation (IP) and liquid chromatography combined with tandem mass spectrometry (LC–MS/MS) methods, while osteoclasts were analyzed through RNA-sequencing. Heterogeneous nuclear ribonucleoprotein K (hnRNPK) was identified as a potential binding partner of Prdx5 during osteoblast differentiation in vitro. Prdx5 acts as a negative regulator of hnRNPK-mediated osteocalcin (Bglap) expression. In addition, transcriptomic analysis revealed that in vitro differentiated osteoclasts from the bone marrow-derived macrophages of Prdx5Ko mice showed enhanced expression of several osteoclast-related genes. These findings indicate that Prdx5 might contribute to the maintenance of bone homeostasis by regulating osteoblast differentiation. This study proposes a new function of Prdx5 in bone remodeling that may be used in developing therapeutic strategies for bone diseases.