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Ferroptosis, but Not Necroptosis, Is Important in Nephrotoxic Folic Acid–Induced AKI
Open accessAbstract
AKI is histologically characterized by necrotic cell death and inflammation. Diverse pathways of regulated necrosis have been reported to contribute to AKI, but the molecular regulators involved remain unclear. We explored the relative contributions of ferroptosis and necroptosis to folic acid (FA)–induced AKI in mice. FA-AKI in mice associates with lipid peroxidation and downregulation of glutathione metabolism proteins, features that are typical of ferroptotic cell death. We show that ferrostatin-1 (Fer-1), an inhibitor of ferroptosis, preserved renal function and decreased histologic injury, oxidative stress, and tubular cell death in this model. With respect to the immunogenicity of ferroptosis, Fer-1 prevented the upregulation of IL-33, an alarmin linked to necroptosis, and other chemokines and cytokines and prevented macrophage infiltration and Klotho downregulation. In contrast, the pancaspase inhibitor zVAD-fmk did not protect against FA-AKI. Additionally, although FA-AKI resulted in increased protein expression of the necroptosis mediators receptor–interacting protein kinase 3 (RIPK3) and mixed lineage domain–like protein (MLKL), targeting necroptosis with the RIPK1 inhibitor necrostatin-1 or genetic deficiency of RIPK3 or MLKL did not preserve renal function. Indeed, compared with wild-type mice, MLKL knockout mice displayed more severe AKI. However, RIPK3 knockout mice with AKI had less inflammation than their wild-type counterparts, and this effect associated with higher IL-10 concentration and regulatory T cell-to-leukocyte ratio in RIPK3 knockout mice. These data suggest that ferroptosis is the primary cause of FA-AKI and that immunogenicity secondary to ferroptosis may further worsen the damage, although necroptosis-related proteins may have additional roles in AKI.
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“A similar protective effect is observed in GPX4-independent models of renal ischemic or toxic injury [540, 592], Parkinson disease [593], and other human pathologies [594].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [592]
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Metadata
- Authors
- Martin-Sanchez, D., Ruiz-Andres, O., Poveda, J., Carrasco, S., Cannata-Ortiz, P., Sanchez-Niño, M. D., Ruiz Ortega, M., Egido, J., Linkermann, A., Ortiz, A., & Sanz, A. B.
- Affiliations
- Division of Nephrology and
- Department of Pathology, Instituto de Investigacion Sanitaria (IIS)-Fundacion Jimenez Diaz and
- Christian-Albrechts-Universität zu Kiel (DE)
- Corresponding author
- Poveda, Jonay
- Carrasco, Susana
- Linkermann, Andreas
- Sanz, Ana B.
- Venue
- Journal of the American Society of Nephrology
- Published
- 2016-06-27
- Volume
- 28
- Issue
- 1
- Pages
- 218-229
- ISSN
- 1046-6673 (ISSN-L)
- 1533-3450
- PMC
- PMC5198282
- OpenAlex
- W2470889344
- Cited by
- 564
- References
- 37
- Citations by year
- 2026: 44 · 2025: 72 · 2024: 84 · 2023: 79 · 2022: 99 · 2021: 65 · 2020: 46 · 2019: 31 · 2018: 31 · 2017: 13
- FWCI
- 24.89
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of the American Society of Nephrology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, other-oa)
- Topics
- Health Sciences › Medicine › Nephrology › Acute Kidney Injury Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Ferroptosis and cancer prognosis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- ferroptosis, necroptosis, acute kidney injury, folic acid nephrotoxicity, ferrostatin-1, regulated necrosis, lipid peroxidation, glutathione metabolism, IL-33, RIPK3, MLKL, necrostatin-1, Klotho, macrophage infiltration, renal inflammation, oxidative stress, regulatory T cells
- MeSH terms
- Animals, Folic Acid, Iron, Mice, Inbred C57BL, Necrosis, Cell Death, Mice, Acute Kidney Injury
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