Please use this identifier to cite or link to this item:
Title: Podocytes are new cellular targets of haemoglobin-mediated renal damage.
Authors: Rubio-Navarro, Alfonso
Sanchez-Niño, Maria Dolores
Guerrero-Hue, Melania
García-Caballero, Cristina
Gutiérrez, Eduardo
Yuste, Claudia
Sevillano, Ángel
Praga, Manuel
Egea, Javier
Román, Elena
Cannata, Pablo
Ortega, Rosa
Cortegano, Isabel
de Andrés, Belén
Gaspar, María Luisa
Cadenas, Susana
Ortiz, Alberto
Egido, Jesús
Moreno, Juan Antonio
Keywords: Nrf2;apoptosis;haemoglobin;intravascular haemolysis;oxidative stress;podocyte
metadata.dc.subject.mesh: Acute Kidney Injury
Anemia, Hemolytic
Cell Line
Disease Models, Animal
Heme Oxygenase-1
Low Density Lipoprotein Receptor-Related Protein-2
Membrane Proteins
Mice, Inbred C57BL
Mice, Knockout
NF-E2-Related Factor 1
NF-E2-Related Factor 2
Oxidative Stress
Receptors, Cell Surface
Young Adult
Issue Date: 10-Jan-2018
Abstract: Recurrent and massive intravascular haemolysis induces proteinuria, glomerulosclerosis, and progressive impairment of renal function, suggesting podocyte injury. However, the effects of haemoglobin (Hb) on podocytes remain unexplored. Our results show that cultured human podocytes or podocytes isolated from murine glomeruli bound and endocytosed Hb through the megalin-cubilin receptor system, thus resulting in increased intracellular Hb catabolism, oxidative stress, activation of the intrinsic apoptosis pathway, and altered podocyte morphology, with decreased expression of the slit diaphragm proteins nephrin and synaptopodin. Hb uptake activated nuclear factor erythroid-2-related factor 2 (Nrf2) and induced expression of the Nrf2-related antioxidant proteins haem oxygenase-1 (HO-1) and ferritin. Nrf2 activation and Hb staining was observed in podocytes of mice with intravascular haemolysis. These mice developed proteinuria and showed podocyte injury, characterized by foot process effacement, decreased synaptopodin and nephrin expression, and podocyte apoptosis. These pathological effects were enhanced in Nrf2-deficient mice, whereas Nrf2 activation with sulphoraphane protected podocytes against Hb toxicity both in vivo and in vitro. Supporting the translational significance of our findings, we observed podocyte damage and podocytes stained for Hb, HO-1, ferritin and phosphorylated Nrf2 in renal sections and urinary sediments of patients with massive intravascular haemolysis, such as atypical haemolytic uraemic syndrome and paroxysmal nocturnal haemoglobinuria. In conclusion, podocytes take up Hb both in vitro and during intravascular haemolysis, promoting oxidative stress, podocyte dysfunction, and apoptosis. Nrf2 may be a potential therapeutic target to prevent loss of renal function in patients with intravascular haemolysis. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
metadata.dc.identifier.doi: 10.1002/path.5011
Appears in Collections:Producción 2020

Files in This Item:
There are no files associated with this item.

This item is protected by original copyright

Except where otherwise noted, Items on the Andalusian Health Repository site are licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives License.