Cytochrome b5 reductase-3 overexpression reduces renal damage associated to intravascular hemolysis
Year: 2026
Type: article
Abstract: Intravascular hemolysis can cause both acute kidney injury (AKI) and chronic kidney disease (CKD). When erythrocytes break down in the bloodstream, they release hemoglobin and heme derivatives, which accumulate in renal cells and lead to increased oxidative stress, inflammation, cell death, and mitochondrial dysfunction. The enzyme NADH-cytochrome b 5 reductase 3 (CYB5R3) plays a role in NAD + metabolism and helps reduce oxidative stress and inflammation while enhancing mitochondrial function. In this study, we examined whether overexpressing CYB5R3 offers kidney protection against AKI caused by intravascular hemolysis and prevents the progression from AKI to CKD, including analysis of sex-based differences. We created an experimental model to assess acute and chronic kidney damage related to intravascular hemolysis in wild-type (WT) and CYB5R3-overexpressing transgenic (TG) mice. Additionally, we performed in vitro experiments to determine if pharmacological induction of CYB5R3 with tetrahydroindenoindole (THII) reduced heme-mediated nephrotoxicity. AKI resulting from intravascular hemolysis impaired kidney function, increased damage to tubular epithelium and podocytes, promoted oxidative stress and inflammation, caused mitochondrial dysfunction, altered autophagy-related markers, and cell death—effects that were more severe in males than females. CYB5R3 overexpression notably diminished these pathological changes and slowed CKD progression by decreasing inflammation and fibrosis, regardless of sex. In cellular systems, induction of CYB5R3 with THII lowered heme-induced reactive oxygen species (ROS) production, inflammation, and cell death, and restored NAD + levels. These protective effects were eliminated by pharmacological inhibition of CYB5R3 activity. Our findings suggest that CYB5R3 could be a promising therapeutic target for preventing AKI related to intravascular hemolysis and its progression to CKD.
Source: Biomedicine & Pharmacotherapy
Authors: Cristina García-Caballero, Luz Marina Sánchez-Mendoza, Mercedes Vallejo-Mudarra, Lucía Beltrán-Camacho, Isabel Pozuelo, Leo Valentín-Aragón, Raquel María García-Saez, Miguel Pérez-Rodríguez, Fernando Leiva-Cepas, José Antonio González-Reyes, Sebastián Mas, Jesús Egido, Rafael de Cabo, José Manuel Villalba, Juan Antonio Moreno
Institutions: Instituto Maimónides de Investigación Biomédica de Córdoba, Hospital Universitario Reina Sofía, University of Córdoba, Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas, Hospital Universitario Fundación Jiménez Díaz, Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Universidad Autónoma de Madrid, National Institutes of Health, National Institute on Aging
Language: English
Topic: Acute Kidney Injury Research
Subfield: Nephrology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,610
Awards: El papel de la inflamación en la prevención de la diabetes tipo 2 y sus complicaciones. La modulación de las vías de señalización inflamatorias como terapia añadida a los nuevos fármacos antidiabéticos., Inflamación como diana terapéutica en las complicaciones de la diabetes tipo 2, Aging Intervention Program, Acumulación de hemoproteínas como responsable de la pérdida aguda y crónica de la función renal. Caracterización de nuevos mecanismos de daño e identificación de posibles dianas terapéuticas., G6418500475, Nuevos mecanismos y dianas terapéuticas implicadas en la progresión del daño renal en patologías asociadas a acumulación de hemoglobina, Aging and CR effects on the Plasma Membrane Redox System
OpenAlex ID: W7161180076