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This research was funded by Instituto de Salud Carlos III (ISCIII) (PI20/00375, PI20/00487, PI23/00119, PI23/00669) (Co-funded by the European Union) , Programa Operativo FEDER Junta de Andalucia (1381179-R) , Consejeria de Salud y Familias-FEDER, Junta de Andalucia (PIGE-0052-2020) , University of Cordoba (BIO-276) . Work in JMVM lab was supported by PID2021-126280OB-I00. The "PFIS" and "Sara Borrell" training programs of the ISCIII supported the salary of MGH (FI18/00310) and CH (CD17/00030) . Spanish Ministerio de Ciencia, Innovacion y Universidades (MCIU) /Agencia Estatal de Investigacion (AEI) /10.13039/501100011033 and "FSE invierte en tu futuro" sup-ported the salary of JAM (Ramon y Cajal RYC-2017-22369) . Cordoba University and Programa Investigo (INVEST_SAE22_031) supported the salary of CGC. Junta de Andalucia (PIGE-0052-2020) and Programa Investigo (INVESTIGO21_023) supported the salary of MVM. MINECO, PRE2019-087438 supported the salary of LMSM.

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Egido, JesusAuthorEgea JAuthor

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November 4, 2024
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Nox4 is involved in acute kidney injury associated to intravascular hemolysis

Publicated to:FREE RADICAL BIOLOGY AND MEDICINE. 225 430-444 - 2024-11-20 225(), DOI: 10.1016/j.freeradbiomed.2024.10.283

Authors: Garcia-Caballero, Cristina; Guerrero-Hue, Melania; Vallejo-Mudarra, Mercedes; Antolin, Alejandra Palomino; Decouty-Perez, Celine; Sanchez-Mendoza, Luz Marina; Villalba, Jose Manuel; Opazo-Rios, Lucas; Vazquez-Carballo, Cristina; Herencia, Carmen; Leiva-Cepas, Fernando; Cortegano, Isabel; Egido, Jesus; Moreno, Juan Antonio

Affiliations

Autonomous Univ Madrid, IIS Fdn Jimenez Diaz, Renal Vasc & Diabet Res Lab, Madrid, Spain - Author
Carlos III Hlth Inst, Immunobiol Dept, Madrid, Spain - Author
Hosp Santa Cristina, Res Unit, Inst Invest Sanitaria Princesa IIS IP, Madrid 28006, Spain - Author
Reina Sofia Univ Hosp, Maimonides Biomed Res Inst Cordoba IMIBIC, Cordoba, Spain - Author
Spanish Biomed Res Ctr Diabet & Associated Metab D, Madrid, Spain - Author
Univ Cordoba, Dept Cell Biol Physiol & Immunol, Campus Int Agrifood Excellence CeiA3, Cordoba, Spain - Author
Univ Cordoba, Hosp Univ Reina Sofia, Fac Med & Nurse, Dept Morphol & Sociosanitary Sci,Pathol Unit, Cordoba, Spain - Author
Univ Las Amer, Hlth Sci Fac, Talcahuano, Concepcion, Chile - Author
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Abstract

Massive intravascular hemolysis occurs not unfrequently in many clinical conditions. Breakdown of erythrocytes promotes the accumulation of heme-derivates in the kidney, increasing oxidative stress and cell death, thus promoting acute kidney injury (AKI). NADPH oxidase 4 (Nox4) is a major source of reactive oxygen species (ROS) in the kidney, however it is unknown the role of Nox4 in hemolysis and whether inhibition of this enzyme may protect from heme-mediated injury. To answer these questions, we elicited intravascular hemolysis in wild type and Nox4 knockout mice. We also evaluated whether nephrotoxic effects of heme may be reduced by using Nox4 siRNA and pharmacologic inhibition with GKT137831, a Nox4 inhibitor, both in vivo and in cultured renal cells. Our results showed that induction of massive hemolysis elicited AKI characterized by loss of renal function, morphological alterations of the tubular epithelium and podocytes, oxidative stress, inflammation, mitochondrial dysfunction, blockade of autophagy and cell death. These pathological effects were significantly prevented in Nox4-deficient mice and in animals treated with GKT137831. In vitro studies showed that Nox4 disruption by

Keywords

AccumulatioCell-deathDiabetic-nephropathyEndoplasmic-reticulum stressHemeIntravascular hemolysisMouse modelNadph oxidase 4Nox4Oxidative stresOxidative stressPharmacological inhibitionRenal damageRenoprotection

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal FREE RADICAL BIOLOGY AND MEDICINE 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, 2024 there are still no calculated indicators, but in 2023, it was in position 14/191, thus managing to position itself as a Q1 (Primer Cuartil), in the category Endocrinology & Metabolism. Notably, the journal is positioned above the 90th percentile.

Independientemente del impacto esperado determinado por el canal de difusión, es importante destacar el impacto real observado de la propia aportación.

Según las diferentes agencias de indexación, el número de citas acumuladas por esta publicación hasta la fecha 2025-10-12:

  • Scopus: 1

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 2025-10-12:

  • 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: 3 (PlumX).

Leadership analysis of institutional authors

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