Podocytes are new cellular targets of haemoglobin‐mediated renal damage |
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Authors: | Alfonso Rubio‐Navarro Maria Dolores Sanchez‐Niño Melania Guerrero‐Hue Cristina García‐Caballero Eduardo Gutiérrez Claudia Yuste Ángel Sevillano Manuel Praga Javier Egea Elena Román Pablo Cannata Rosa Ortega Isabel Cortegano Belén de Andrés María Luisa Gaspar Susana Cadenas Alberto Ortiz Jesús Egido Juan Antonio Moreno |
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Institution: | 1. Renal, Vascular and Diabetes Research Laboratory, Fundación Instituto de Investigación Sanitaria‐Fundación Jiménez Díaz, Autónoma University, Madrid, Spain;2. Red de Investigación Renal (REDINREN), Madrid, Spain;3. Department of Nephrology, Hospital 12 de Octubre, Madrid, Spain;4. Instituto de Investigación Sanitaria‐Hospital Universitario de la Princesa, Madrid, Spain;5. Instituto Teófilo Hernando, Department of Pharmacology and Therapeutics, Medicine Faculty, Autónoma University, Madrid, Spain;6. Paediatric Nephrology Department, La Fe Hospital, Valencia, Spain;7. Pathology Department, Fundación Instituto de Investigaciones Sanitarias‐Fundación Jiménez Díaz, Autónoma University, Madrid, Spain;8. Pathology Department, Hospital Universitario Reina Sofia, Córdoba, Spain;9. Immunology Department, Centro Nacional de Microbiología, Instituto de Salud Carlos III (ISCIII), Madrid, Spain;10. Centro de Biología Molecular ‘Severo Ochoa’ and Molecular Biology Department, Autónoma University, Madrid, Spain;11. Instituto de Investigación Sanitaria La Princesa, Madrid, Spain;12. Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain |
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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. |
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Keywords: | intravascular haemolysis haemoglobin podocyte oxidative stress apoptosis Nrf2 |
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