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Front Pharmacol. 2019 Jul 3;10:740. doi: 10.3389/fphar.2019.00740. eCollection 2019.

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

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Renal, Vascular and Diabetes Research Lab, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz, Autónoma University, Madrid, Spain.
Department of Nephrology, Hospital 12 de Octubre, Madrid, Spain.
Instituto de Investigación Sanitaria-Hospital Universitario de la Princesa, Madrid, Spain.
Instituto Teófilo Hernando, Departamento de Farmacología y Terapéutica, Facultad de Medicina, UAM, Madrid, Spain.
Hospital Santa Cristina, Madrid, Spain.
Pathology Department, Fundación Instituto de Investigaciones Sanitarias-Fundación Jiménez Díaz, Autónoma University, Madrid, Spain.
Immunology Department, Centro Nacional de Microbiologìa, Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Departamento de Biología Molecular, Universidad Autónoma de Madrid, Madrid, Spain.
Department of Cell Biology, Physiology and Immunology, Maimonides Biomedical Research Institute of Cordoba (IMIBIC), University of Cordoba, Cordoba, Spain.


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.


Nrf2; heme; hemoglobin; intravascular hemolysis; oxidative stress; sulforaphane; tubular injury

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