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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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Nox4 is involved in acute kidney injury associated to intravascular hemolysis

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

Autores: 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

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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

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