Targeting the TWEAK–Fn14 pathway prevents dysfunction in cardiac calcium handling after acute kidney injury

Heart and kidney have a closely interrelated pathophysiology. Acute kidney injury (AKI) is associated with significantly increased rates of cardiovascular events, a relationship defined as cardiorenal syndrome type 3 (CRS3). The underlying mechanisms that trigger heart disease remain, however, unkno...

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Autores: Poveda, Jonay, González Lafuente, Laura, Vázquez Sánchez, Sara, Mercado García, Elisa, Rodríguez Sánchez, Elena, García Consuegra, Inés, Sanz Bartolomé, Ana Belén, Segura, Julián, Fernández Velasco, María, Liaño, Fernando, Ruilope, Luis Miguel, Ruiz Hurtado, Gema
Tipo de recurso: artículo
Fecha de publicación:2023
País:España
Institución:Universidad Autónoma de Madrid
Repositorio:Biblos-e Archivo. Repositorio Institucional de la UAM
Idioma:inglés
OAI Identifier:oai:repositorio.uam.es:10486/708905
Acceso en línea:http://hdl.handle.net/10486/708905
https://dx.doi.org/10.1002/path.6200
Access Level:acceso abierto
Palabra clave:Acute kidney injurye
Calcium mishandling
Cardiomyocyte
Cardiorenal syndrome
Renal ischaemia/reperfusion
TWEAK–Fn14 pathway
Medicina
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spelling Targeting the TWEAK–Fn14 pathway prevents dysfunction in cardiac calcium handling after acute kidney injuryPoveda, JonayGonzález Lafuente, LauraVázquez Sánchez, SaraMercado García, ElisaRodríguez Sánchez, ElenaGarcía Consuegra, InésSanz Bartolomé, Ana BelénSegura, JuliánFernández Velasco, MaríaLiaño, FernandoRuilope, Luis MiguelRuiz Hurtado, GemaAcute kidney injuryeCalcium mishandlingCardiomyocyteCardiorenal syndromeRenal ischaemia/reperfusionTWEAK–Fn14 pathwayMedicinaHeart and kidney have a closely interrelated pathophysiology. Acute kidney injury (AKI) is associated with significantly increased rates of cardiovascular events, a relationship defined as cardiorenal syndrome type 3 (CRS3). The underlying mechanisms that trigger heart disease remain, however, unknown, particularly concerning the clinical impact of AKI on cardiac outcomes and overall mortality. Tumour necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor fibroblast growth factor-inducible 14 (Fn14) are independently involved in the pathogenesis of both heart and kidney failure, and recent studies have proposed TWEAK as a possible therapeutic target; however, its specific role in cardiac damage associated with CRS3 remains to be clarified. Firstly, we demonstrated in a retrospective longitudinal clinical study that soluble TWEAK plasma levels were a predictive biomarker of mortality in patients with AKI. Furthermore, the exogenous application of TWEAK to native ventricular cardiomyocytes induced relevant calcium (Ca2+) handling alterations. Next, we investigated the role of the TWEAK–Fn14 axis in cardiomyocyte function following renal ischaemia–reperfusion (I/R) injury in mice. We observed that TWEAK–Fn14 signalling was activated in the hearts of AKI mice. Mice also showed significantly altered intra-cardiomyocyte Ca2+ handling and arrhythmogenic Ca2+ events through an impairment in sarcoplasmic reticulum Ca2+-adenosine triphosphatase 2a pump (SERCA2a) and ryanodine receptor (RyR2) function. Administration of anti-TWEAK antibody after reperfusion significantly improved alterations in Ca2+ cycling and arrhythmogenic events and prevented SERCA2a and RyR2 modifications. In conclusion, this study establishes the relevance of the TWEAK–Fn14 pathway in cardiac dysfunction linked to CRS3, both as a predictor of mortality in patients with AKI and as a Ca2+ mishandling inducer in cardiomyocytes, and highlights the cardioprotective benefits of TWEAK targeting in CRS3This work was mainly supported by projects from the Instituto de Salud Carlos III (ISCIII) (PI20/00763, PI20/01482, CPII20/00022, FI18/00261, FI21/00212, CD19/00029, IFEQ21/00012, PI19/00588, PI22/00469) and co-funded by the European Union, Ministerio de Universidades (FPU20/03005), Ministerio de Ciencia e Innovaci on (RYR2019-026916-I), the Education and Research Council of Madrid (PEJ-2021- AI/SAL-21426), Biomedicine Network Comunidad de Madrid (P2022/BMD-7223 CIFRA_COR-CM), Spanish Network in Inflammasoma and Pyroptosis in Chronic Disease and Cancer (RED2022-134511-T), and the Spanish Society of Nephrology SEN/SENEFRO FoundationWileyDepartamento de FisiologíaFacultad de Medicina20232023-09-30research articlehttp://purl.org/coar/resource_type/c_2df8fbb1VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10486/708905https://dx.doi.org/10.1002/path.6200reponame:Biblos-e Archivo. Repositorio Institucional de la UAMinstname:Universidad Autónoma de MadridInglésengopen accesshttp://purl.org/coar/access_right/c_abf2info:eu-repo/semantics/openAccessoai:repositorio.uam.es:10486/7089052026-06-23T12:46:27Z
dc.title.none.fl_str_mv Targeting the TWEAK–Fn14 pathway prevents dysfunction in cardiac calcium handling after acute kidney injury
title Targeting the TWEAK–Fn14 pathway prevents dysfunction in cardiac calcium handling after acute kidney injury
spellingShingle Targeting the TWEAK–Fn14 pathway prevents dysfunction in cardiac calcium handling after acute kidney injury
Poveda, Jonay
Acute kidney injurye
Calcium mishandling
Cardiomyocyte
Cardiorenal syndrome
Renal ischaemia/reperfusion
TWEAK–Fn14 pathway
Medicina
title_short Targeting the TWEAK–Fn14 pathway prevents dysfunction in cardiac calcium handling after acute kidney injury
title_full Targeting the TWEAK–Fn14 pathway prevents dysfunction in cardiac calcium handling after acute kidney injury
title_fullStr Targeting the TWEAK–Fn14 pathway prevents dysfunction in cardiac calcium handling after acute kidney injury
title_full_unstemmed Targeting the TWEAK–Fn14 pathway prevents dysfunction in cardiac calcium handling after acute kidney injury
title_sort Targeting the TWEAK–Fn14 pathway prevents dysfunction in cardiac calcium handling after acute kidney injury
dc.creator.none.fl_str_mv Poveda, Jonay
González Lafuente, Laura
Vázquez Sánchez, Sara
Mercado García, Elisa
Rodríguez Sánchez, Elena
García Consuegra, Inés
Sanz Bartolomé, Ana Belén
Segura, Julián
Fernández Velasco, María
Liaño, Fernando
Ruilope, Luis Miguel
Ruiz Hurtado, Gema
author Poveda, Jonay
author_facet Poveda, Jonay
González Lafuente, Laura
Vázquez Sánchez, Sara
Mercado García, Elisa
Rodríguez Sánchez, Elena
García Consuegra, Inés
Sanz Bartolomé, Ana Belén
Segura, Julián
Fernández Velasco, María
Liaño, Fernando
Ruilope, Luis Miguel
Ruiz Hurtado, Gema
author_role author
author2 González Lafuente, Laura
Vázquez Sánchez, Sara
Mercado García, Elisa
Rodríguez Sánchez, Elena
García Consuegra, Inés
Sanz Bartolomé, Ana Belén
Segura, Julián
Fernández Velasco, María
Liaño, Fernando
Ruilope, Luis Miguel
Ruiz Hurtado, Gema
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Departamento de Fisiología
Facultad de Medicina
dc.subject.none.fl_str_mv Acute kidney injurye
Calcium mishandling
Cardiomyocyte
Cardiorenal syndrome
Renal ischaemia/reperfusion
TWEAK–Fn14 pathway
Medicina
topic Acute kidney injurye
Calcium mishandling
Cardiomyocyte
Cardiorenal syndrome
Renal ischaemia/reperfusion
TWEAK–Fn14 pathway
Medicina
description Heart and kidney have a closely interrelated pathophysiology. Acute kidney injury (AKI) is associated with significantly increased rates of cardiovascular events, a relationship defined as cardiorenal syndrome type 3 (CRS3). The underlying mechanisms that trigger heart disease remain, however, unknown, particularly concerning the clinical impact of AKI on cardiac outcomes and overall mortality. Tumour necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor fibroblast growth factor-inducible 14 (Fn14) are independently involved in the pathogenesis of both heart and kidney failure, and recent studies have proposed TWEAK as a possible therapeutic target; however, its specific role in cardiac damage associated with CRS3 remains to be clarified. Firstly, we demonstrated in a retrospective longitudinal clinical study that soluble TWEAK plasma levels were a predictive biomarker of mortality in patients with AKI. Furthermore, the exogenous application of TWEAK to native ventricular cardiomyocytes induced relevant calcium (Ca2+) handling alterations. Next, we investigated the role of the TWEAK–Fn14 axis in cardiomyocyte function following renal ischaemia–reperfusion (I/R) injury in mice. We observed that TWEAK–Fn14 signalling was activated in the hearts of AKI mice. Mice also showed significantly altered intra-cardiomyocyte Ca2+ handling and arrhythmogenic Ca2+ events through an impairment in sarcoplasmic reticulum Ca2+-adenosine triphosphatase 2a pump (SERCA2a) and ryanodine receptor (RyR2) function. Administration of anti-TWEAK antibody after reperfusion significantly improved alterations in Ca2+ cycling and arrhythmogenic events and prevented SERCA2a and RyR2 modifications. In conclusion, this study establishes the relevance of the TWEAK–Fn14 pathway in cardiac dysfunction linked to CRS3, both as a predictor of mortality in patients with AKI and as a Ca2+ mishandling inducer in cardiomyocytes, and highlights the cardioprotective benefits of TWEAK targeting in CRS3
publishDate 2023
dc.date.none.fl_str_mv 2023
2023-09-30
dc.type.none.fl_str_mv research article
http://purl.org/coar/resource_type/c_2df8fbb1
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/10486/708905
https://dx.doi.org/10.1002/path.6200
url http://hdl.handle.net/10486/708905
https://dx.doi.org/10.1002/path.6200
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Wiley
publisher.none.fl_str_mv Wiley
dc.source.none.fl_str_mv reponame:Biblos-e Archivo. Repositorio Institucional de la UAM
instname:Universidad Autónoma de Madrid
instname_str Universidad Autónoma de Madrid
reponame_str Biblos-e Archivo. Repositorio Institucional de la UAM
collection Biblos-e Archivo. Repositorio Institucional de la UAM
repository.name.fl_str_mv
repository.mail.fl_str_mv
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