Tweak/Fn14 system is involved in rhabdomyolysis-induced acute kidney injury.

Autor: Guerrero-Hue M; Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Hospital Universitario Reina Sofía, Cordoba, Spain., Vallejo-Mudarra M; Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Hospital Universitario Reina Sofía, Cordoba, Spain., García-Caballero C; Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Hospital Universitario Reina Sofía, Cordoba, Spain., Córdoba-David GM; Renal, Vascular and Diabetes Research Lab, Fundación Instituto de Investigaciones Sanitarias-Fundación Jiménez Díaz, Autonoma University, Madrid, Spain., Palomino-Antolín A; Molecular Neuroinflammation and Neuronal Plasticity Research Laboratory, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria-Hospital Universitario de la Princesa, Madrid, Spain; Instituto Teófilo Hernando, Departamento de Farmacología y Terapéutica, Facultad de Medicina, Autonoma University, Madrid, Spain., Herencia C; Renal, Vascular and Diabetes Research Lab, Fundación Instituto de Investigaciones Sanitarias-Fundación Jiménez Díaz, Autonoma University, Madrid, Spain., Vendrell-Casana B; Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Hospital Universitario Reina Sofía, Cordoba, Spain., Rubio-Navarro A; Laboratory of Advanced Therapies: Differentiation, Regeneration and Cancer (CTS-963). Center of Biomedical Research. University of Granada, Spain; Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), Granada, Spain; Excellence Research Unit 'Modeling Nature' (MNat), University of Granada, Granada, Spain., Egido J; Renal, Vascular and Diabetes Research Lab, Fundación Instituto de Investigaciones Sanitarias-Fundación Jiménez Díaz, Autonoma University, Madrid, Spain; Centre of Biomedical Research in Network of Diabetes and Metabolic Disease Associated (CIBERDEM), Madrid, Spain., Blanco-Colio LM; Renal, Vascular and Diabetes Research Lab, Fundación Instituto de Investigaciones Sanitarias-Fundación Jiménez Díaz, Autonoma University, Madrid, Spain; Centre of Biomedical Research in Network of Cardiovascular Diseases (CIBERCV), Madrid, Spain., Moreno JA; Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Hospital Universitario Reina Sofía, Cordoba, Spain; Centre of Biomedical Research in Network of Cardiovascular Diseases (CIBERCV), Madrid, Spain; Department of Cell Biology, Physiology and Immunology, University of Cordoba, Cordoba, Spain. Electronic address: juan.moreno@uco.es.
Jazyk: angličtina
Zdroj: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie [Biomed Pharmacother] 2023 Dec 31; Vol. 169, pp. 115925. Date of Electronic Publication: 2023 Nov 25.
DOI: 10.1016/j.biopha.2023.115925
Abstrakt: Background: Rhabdomyolysis is a severe clinical syndrome associated to acute kidney injury (AKI) and chronic kidney disease (CKD). TWEAK/Fn14 signaling axis regulates renal inflammation and tubular cell death. However, the functional role of TWEAK/Fn14 in rhabdomyolysis remains unknown.
Methods: Rhabdomyolysis was induced in wild-type, TWEAK- and Fn14-deficient mice or mice treated with TWEAK blocking antibody. Renal injury, inflammation, fibrosis and cell death were assessed. Additionally, we performed in vivo and in vitro studies to explore the possible signalling pathways involved in Fn14 regulation.
Findings: Fn14 renal expression was increased in mice with rhabdomyolysis, correlating with decline of renal function. Mechanistically, myoglobin (Mb) induced Fn14 expression via ERK and p38 pathway, whereas Nrf2 activation diminished Mb-mediated Fn14 upregulation in cultured renal cells. TWEAK or Fn14 genetic depletion ameliorated rhabdomyolysis-associated loss of renal function, histological damage, tubular cell death, inflammation, and expression of both tubular and endothelial injury markers. Deficiency of TWEAK or Fn14 also decreased long-term renal inflammation and fibrosis in mice with rhabdomyolysis. Finally, pharmacological treatment with a blocking TWEAK antibody diminished the expression of acute renal injury markers and cell death and lessened residual kidney fibrosis and chronic inflammation in rhabdomyolysis.
Interpretation: TWEAK/Fn14 axis participates in the pathogenesis of rhabdomyolysis-AKI and subsequent AKI-CKD transition. Blockade of this signaling pathway may represent a promising therapeutic strategy for reducing rhabdomyolysis-mediated renal injury.
Funding: Spanish Ministry of Science and Innovation, ISCIII and Junta de Andalucía.
Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest.
(Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
Databáze: MEDLINE
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