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Supported by FIS/FEDER CP14/00008, CP16/00014, CP16/00017, PI15/00448, PI16/00735, PI16/02057, PI17/00130, PI17/01495, PI17/01700, ISCIII-RETIC REDinREN RD012/0021, RD016/0009 FEDER funds, Spanish Ministry of Economy and Competitiveness (RYC-2017-22369), Sociedad Espanola de Nefrologia, Fundacion Renal Inigo Alvarez de Toledo (FRIAT), Comunidad de Madrid CIFRA2 B2017/BMD-3686 and BMD-3827, Fundacion La Caixa, CaixaImpulse program CI17-00048, and Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM).

Analysis of institutional authors

Egea, JavierAuthorCannata, PabloAuthorCadenas, SusanaAuthorMichalska, PatrycjaAuthorLeon, RafaelAuthorOrtiz, AlbertoAuthorEgido, JesusAuthor

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July 16, 2019
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Article

Nrf2 Plays a Protective Role Against Intravascular Hemolysis-Mediated Acute Kidney Injury

Publicated to:Frontiers in Pharmacology. 10 (740): 740- - 2019-07-03 10(740), DOI: 10.3389/fphar.2019.00740

Authors: Rubio-Navarro, Alfonso; Vazquez-Carballo, Cristina; Guerrero-Hue, Melania; Garcia-Caballero, Cristina; Herencia, Carmen; Gutierrez, Eduardo; Yuste, Claudia; Sevillano, Angel; Praga, Manuel; Egea, Javier; Cannata, Pablo; Cortegano, Isabel; de Andres, Belen; Luisa Gaspar, Maria; Cadenas, Susana; Michalska, Patrycja; Leon, Rafael; Ortiz, Alberto; Egido, Jesus; Antonio Moreno, Juan;

Affiliations

Cornell Univ, Weill Cornell Med, Dept Med, New York, NY 10021 USA - Author
Hosp 12 Octubre, Dept Nephrol, Madrid, Spain - Author
Hosp Santa Cristina, Madrid, Spain - Author
Hosp Univ Princesa, Inst Invest Sanitaria, Madrid, Spain - Author
ISCIII, Ctr Nacl Microbiol, Dept Immunol, Madrid, Spain - Author
UAM, Fac Med, Inst Teofilo Hernando, Dept Farmacol & Terapeut, Madrid, Spain - Author
Univ Autonoma Madrid, Dept Biol Mol, Ctr Biol Mol Severo Ochoa, CSIC, Madrid, Spain - Author
Univ Autonoma Madrid, Fdn Jimenez Diaz, Fdn Inst Invest Sanitarias, Dept Pathol, Madrid, Spain - Author
Univ Autonoma Madrid, Inst Invest Sanitaria, Fdn Jimenez Diaz, Renal Vasc & Diabet Res Lab, Madrid, Spain - Author
Univ Cordoba, Dept Cell Biol Physiol & Immunol, Maimonides Biomed Res Inst Cordoba IMIBIC, Cordoba, Spain - Author
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Abstract

Massive intravascular hemolysis is associated with acute kidney injury (AKI). Nuclear factor erythroid-2-related factor 2 (Nrf2) plays a central role in the defense against oxidative stress by activating the expression of antioxidant proteins. We investigated the role of Nrf2 in intravascular hemolysis and whether Nrf2 activation protected against hemoglobin (Hb)/heme-mediated renal damage in vivo and in vitro. We observed renal Nrf2 activation in human hemolysis and in an experimental model of intravascular hemolysis promoted by phenylhydrazine intraperitoneal injection. In wild-type mice, Hb/heme released from intravascular hemolysis promoted AKI, resulting in decreased renal function, enhanced expression of tubular injury markers (KIM-1 and NGAL), oxidative and endoplasmic reticulum stress (ER), and cell death. These features were more severe in Nrf2-deficient mice, which showed decreased expression of Nrf2-related antioxidant enzymes, including heme oxygenase 1 (HO-1) and ferritin. Nrf2 activation with sulforaphane protected against Hb toxicity in mice and cultured tubular epithelial cells, ameliorating renal function and kidney injury and reducing cell stress and death. Nrf2 genotype or sulforaphane treatment did not influence the severity of hemolysis. In conclusion, our study identifies Nrf2 as a key molecule involved in protection against renal damage associated with hemolysis and opens novel therapeutic approaches to prevent renal damage in patients with severe hemolytic crisis. These findings provide new insights into novel aspects of Hb-mediated renal toxicity and may have important therapeutic implications for intravascular hemolysis-related diseases.

Keywords

hemehemoglobinintravascular hemolysisnrf2oxidative stresssulforaphaneActivationEndoplasmic-reticulum stressFerritinFree hemoglobinHemeHeme oxygenase-1HemoglobinInductionIntravascular hemolysisNrf2Oxidative stressRhabdomyolysisSickle-cell-diseaseSulforaphaneTranscription factor nrf2Tubular injury

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal Frontiers in Pharmacology 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, 2019, it was in position 52/271, thus managing to position itself as a Q1 (Primer Cuartil), in the category Pharmacology & Pharmacy.

From a relative perspective, and based on the normalized impact indicator calculated from World Citations provided by WoS (ESI, Clarivate), it yields a value for the citation normalization relative to the expected citation rate of: 1.95. This indicates that, compared to works in the same discipline and in the same year of publication, it ranks as a work cited above average. (source consulted: ESI Nov 14, 2024)

This information is reinforced by other indicators of the same type, which, although dynamic over time and dependent on the set of average global citations at the time of their calculation, consistently position the work at some point among the top 50% most cited in its field:

  • Weighted Average of Normalized Impact by the Scopus agency: 2.86 (source consulted: FECYT Feb 2024)
  • Field Citation Ratio (FCR) from Dimensions: 11.93 (source consulted: Dimensions Aug 2025)

Specifically, and according to different indexing agencies, this work has accumulated citations as of 2025-08-05, the following number of citations:

  • WoS: 32
  • Scopus: 40
  • Europe PMC: 25

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 2025-08-05:

  • 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: 43.
  • 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: 50 (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: 4.5.
  • The number of mentions on the social network X (formerly Twitter): 10 (Altmetric).

It is essential to present evidence supporting full alignment with institutional principles and guidelines on Open Science and the Conservation and Dissemination of Intellectual Heritage. A clear example of this is:

  • The work has been submitted to a journal whose editorial policy allows open Open Access publication.

Leadership analysis of institutional authors

This work has been carried out with international collaboration, specifically with researchers from: United States of America.

There is a significant leadership presence as some of the institution’s authors appear as the first or last signer, detailed as follows: First Author (Rubio-Navarro, Alfonso) and Last Author (Antonio Moreno, Juan).

the authors responsible for correspondence tasks have been Rubio-Navarro, Alfonso and Antonio Moreno, Juan.