Cited by 566Acute Kidney Injury ResearchFerroptosis and cancer prognosisCell death mechanisms and regulation

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Ferroptosis, but Not Necroptosis, Is Important in Nephrotoxic Folic Acid–Induced AKI

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Martin-Sanchez, Diego, Ruiz-Andres, Olga, Poveda, Jonay, Carrasco, Susana, Cannata-Ortiz, Pablo, Sanchez-Niño, Maria D., Ruiz Ortega, Marta, Egido, Jesus, Linkermann, Andreas, Ortiz, Alberto, Sanz, Ana B.·2017·Journal of the American Society of Nephrology

DOI 10.1681/asn.2015121376PMC PMC5198282

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Abstract

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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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.
ORCID: Poveda, Jonay
Carrasco, Susana
Linkermann, Andreas
Sanz, Ana B.
Venue: Journal of the American Society of Nephrology
Publisher: Ovid Technologies (Wolters Kluwer Health)
Published: 2016-06-27
Volume: 28
Issue: 1
Pages: 218-229
ISSN: 1046-6673 (ISSN-L)
1533-3450
DOI: 10.1681/asn.2015121376
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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Ferroptosis, but Not Necroptosis, Is Important in Nephrotoxic Folic Acid–Induced AKI

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