Ferroptotic stress promotes the accumulation of pro-inflammatory proximal tubular cells in maladaptive renal repair
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.
Sequencing data have been deposited in GEO under accession codes GSE161201. Primer sequence information is available in the supplementary file.
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Article and author information
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.
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.
- Gregory G Germino, National Institutes of Health, United States
- Received: March 20, 2021
- Preprint posted: March 23, 2021 (view preprint)
- Accepted: July 17, 2021
- Accepted Manuscript published: July 19, 2021 (version 1)
- Version of Record published: July 28, 2021 (version 2)
© 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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