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Podocytes are new cellular targets of haemoglobin-mediated renal damage

Data de publicació:

Autors de IIS La Fe

Autors aliens a IIS La Fe

  • Rubio-Navarro, A
  • Sanchez-Nino, MD
  • Guerrero-Hue, M
  • Garcia-Caballero, C
  • Gutierrez, E
  • Yuste, C
  • Sevillano, A
  • Praga, M
  • Egea, J
  • Cannata, P
  • Ortega, R
  • Cortegano, I
  • de Andres, B
  • Gaspar, ML
  • Cadenas, S
  • Ortiz, A
  • Egido, J
  • Moreno, JA

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 (C) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Dades de la publicació

ISSN/ISSNe:
0022-3417, 1096-9896

JOURNAL OF PATHOLOGY  WILEY

Tipus:
Article
Pàgines:
296-310
PubMed:
29205354
Factor d'Impacte:
2,900 SCImago ℠
Quartil:
Q1 SCImago ℠

Cites Rebudes en Web of Science: 40

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Keywords

  • intravascular haemolysis; haemoglobin; podocyte; oxidative stress; apoptosis; Nrf2

Projectes associats

DIAGNÓSTICO GENÉTICO MOLECULAR DE LAS CILIOPATÍAS RENALES MEDIANTE SECUENCIACIÓN MASIVA DE NUEVA GENERACIÓN (NGS).

Investigador Principal: MARIA JOSE APARISI NAVARRO

GV/2016/057 . 2016

REGISTRO NACIONAL DE RECHAZO HUMORAL: ESTUDIO EPIDEMIOLOGICO MULTICENTRICO OBSERVACIONAL PROSPECTIVO PARA EVALUAR LAS CARACTERISTICAS CLINICAS, SEROLOGICAS E HISTOLOGICAS Y LA EVOLUCION A 5 AÑOS DEL RECHAZO HUMORAL POST-TRASPLANTE RENAL EN ESPAÑA

Investigador Principal: ISABEL BENEYTO CASTELLO

HUMORAL-KTX . 2011

UN ESTUDIO OBSERVACIONAL, NO INTERVENCIONISTA, MULTICÉNTRICO Y MULTINACIONAL DE PACIENTES CON SÍNDROME HEMOLÍTICO URÉMICO ATÍPICO (REGISTRO DE SHUA).

Investigador Principal: ELENA ROMÁN ORTIZ

ALE-ECU-2012-01 . 2013

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