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Grant support

This work was supported by Instituto de Salud Carlos III (ISCIII) and Fondo Europeo de Desarrollo Regional grants: PI13/00047, EUTOX, CP12/03262, CP14/00133, PI15/00298, and PI14/00386; Diabetes Cancer Connect grant PIE13/00051; Sociedad Espanola de Nefrologia; Fundacion Renal Inigo Alvarez de Toledo; ISCIII-Redes Tematicas de Investigacion Cooperativa en Salud, Red de Investigacion Renal grant RD012/0021; Comunidad de Madrid (CAM) Consorcio de Investigacion en Fracaso Renal Agudo grant S2010/BMD-2378; and Kidney Connect grant FP7-HEALTH-2013-INNOVATION-1-602422 e-PREDICE. Salary support was from Fundacion Conchita Rabago (to D.M.-S.), ISCIII Miguel Servet (to M.D.S.-N. and A.B.S.), and Programa Intensificacion Actividad Investigadora (ISCIII/Agencia Lain-Entralgo/CAM; to A.O.). A.L. is supported by German Research Foundation in the Cluster of Excellence Inflammation at Interfaces grant EXC306.

Analysis of institutional authors

Sánchez Niño, María DoloresAuthorPoveda, JonayAuthorCannata-Ortiz, PabloAuthorRuiz Ortega, MartaAuthorEgido, JesusAuthorOrtiz, AlbertoAuthorSanz, Ana B.Corresponding Author

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February 14, 2017
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Ferroptosis, but Not Necroptosis, Is Important in Nephrotoxic Folic Acid-Induced AKI

Publicated to:JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY. 28 (1): 218-229 - 2017-01-01 28(1), DOI: 10.1681/ASN.2015121376

Authors: Martin-Sanchez, Diego; Ruiz-Andres, Olga; Poveda, Jonay; Carrasco, Susana; Cannata-Ortiz, Pablo; Sanchez-Nino, Maria D; Ruiz Ortega, Marta; Egido, Jesus; Linkermann, Andreas; Ortiz, Alberto; Sanz, Ana B

Affiliations

Inst Invest Sanitaria IIS Fdn Jimenez Diaz, Dept Pathol, Madrid, Spain      Fundacion Jimenez Diaz - Author
Inst Invest Sanitaria IIS Fdn Jimenez Diaz, Div Nephrol, Madrid, Spain      Fundacion Jimenez Diaz - Author
Inst Invest Sanitaria IIS Fdn Jimenez Diaz, Lab Nephrol, Avda Reyes Catolicos 2, Madrid 28040, Spain.      Fundacion Jimenez Diaz - Author
IRSIN, Madrid, Spain       - Author
Red Invest Renal REDINREN, Madrid, Spain       - Author
Spanish Biomed Res Ctr Diabet & Associated Metab, Madrid, Spain - Author
Univ Autonoma Madrid, Sch Med, Dept Med, Madrid, Spain      Autonomous University of Madrid       - Author
Univ Kiel, Clin Nephrol & Hypertens, Kiel, Germany      University of Kiel - Author
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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.Copyright © 2016 by the American Society of Nephrology.

Keywords

acute renal failurecell deathferroptosisil-33inflammationAcute kidney injuryCell-deathDamageDiseaseExpressionInflammationKinaseNecrosisNf-kappa-bRenal proximal tubule cellTweak

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2017, it was in position 3/76, thus managing to position itself as a Q1 (Primer Cuartil), in the category Urology & Nephrology. Notably, the journal is positioned above the 90th percentile.

This publication has been distinguished as a “Highly Cited Paper” by the agencies WoS (ESI, Clarivate) and ESI (Clarivate), meaning that it ranks within the top 1% of the most cited articles in its thematic field during the year of its publication. In terms of the observed impact of the contribution, this work is considered one of the most influential worldwide, as it is recognized as highly cited. (source consulted: ESI Nov 14, 2024)

And this is evidenced by the extremely high normalized impacts through some of the main indicators of this type, which, although dynamic over time and dependent on the set of average global citations at the time of calculation, already indicate that they are well above the average in different agencies:

  • Normalization of citations relative to the expected citation rate (ESI) by the Clarivate agency: 19.67 (source consulted: ESI Nov 14, 2024)
  • Weighted Average of Normalized Impact by the Scopus agency: 100 (source consulted: FECYT Feb 2024)
  • Field Citation Ratio (FCR) from Dimensions: 108.25 (source consulted: Dimensions Jul 2025)

Specifically, and according to different indexing agencies, this work has accumulated citations as of 2025-07-18, the following number of citations:

  • WoS: 399
  • Scopus: 440
  • Europe PMC: 232
  • Google Scholar: 458

Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-07-18:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 207.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 209 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 2.25.
  • The number of mentions on the social network X (formerly Twitter): 5 (Altmetric).

Leadership analysis of institutional authors

This work has been carried out with international collaboration, specifically with researchers from: Germany.

There is a significant leadership presence as some of the institution’s authors appear as the first or last signer, detailed as follows: Last Author (SANZ BARTOLOME, ANA BELEN).

the author responsible for correspondence tasks has been SANZ BARTOLOME, ANA BELEN.