Ferroptotic stress promotes the accumulation of pro-inflammatory proximal tubular cells in maladaptive renal repair
- Duke University School of Medicine, United States
- Duke University, United States
- 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 use of cold active proteases can dramatically reduce single cell RNA-seq gene expression artifactsNCBI Gene Expression Omnibus, GSE94333.
-
The Single Cell Transcriptomic Landscape of Early Human Diabetic NephropathyNCBI Gene Expression Omnibus, GSE131882.
-
Single Cell Transcriptional Analysis of Donor and Recipient Immune Cell Chimerism in the Rejecting Kidney TransplantNCBI Gene Expression Omnibus, GSE145927.
Article and author information
Author details
Purushothama Rao Tata
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
- 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
- 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)
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
-
- 4,443
- views
-
- 766
- downloads
-
- 73
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
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)
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
-
- Cancer Biology
- Cell Biology
Establishing a zebrafish model of a deadly type of brain tumor highlights the role of the immune system in the early stages of the disease.
-
- Cell Biology
- Neuroscience
One of the most extensively studied members of the Ras superfamily of small GTPases, Rac1 is an intracellular signal transducer that remodels actin and phosphorylation signaling networks. Previous studies have shown that Rac1-mediated signaling is associated with hippocampal-dependent working memory and longer-term forms of learning and memory and that Rac1 can modulate forms of both pre- and postsynaptic plasticity. How these different cognitive functions and forms of plasticity mediated by Rac1 are linked, however, is unclear. Here, we show that spatial working memory in mice is selectively impaired following the expression of a genetically encoded Rac1 inhibitor at presynaptic terminals, while longer-term cognitive processes are affected by Rac1 inhibition at postsynaptic sites. To investigate the regulatory mechanisms of this presynaptic process, we leveraged new advances in mass spectrometry to identify the proteomic and post-translational landscape of presynaptic Rac1 signaling. We identified serine/threonine kinases and phosphorylated cytoskeletal signaling and synaptic vesicle proteins enriched with active Rac1. The phosphorylated sites in these proteins are at positions likely to have regulatory effects on synaptic vesicles. Consistent with this, we also report changes in the distribution and morphology of synaptic vesicles and in postsynaptic ultrastructure following presynaptic Rac1 inhibition. Overall, this study reveals a previously unrecognized presynaptic role of Rac1 signaling in cognitive processes and provides insights into its potential regulatory mechanisms.
