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

被引:0
|
作者
Poveda, Jonay [1 ,11 ]
Gonzalez-Lafuente, Laura [1 ]
Vazquez-Sanchez, Sara [1 ]
Mercado-Garcia, Elisa [1 ]
Rodriguez-Sanchez, Elena [1 ]
Garcia-Consuegra, Ines [2 ]
Sanz, Ana Belen [3 ,4 ]
Segura, Julian [1 ,5 ]
Fernandez-Velasco, Maria [6 ]
Liano, Fernando [7 ]
Ruilope, Luis M. [1 ,8 ,9 ]
Ruiz-Hurtado, Gema [1 ,8 ,10 ,12 ]
机构
[1] Hosp Univ 12 Octubre, Inst Res Imas12, Cardiorenal Translat Lab, Madrid, Spain
[2] Hosp Univ 12 Octubre, Inst Res Imas12, Prote Unit, Madrid, Spain
[3] Autonomous Univ Madrid, IIS Fdn Jimenez Diaz, Nephrol Lab, Madrid, Spain
[4] REDINREN, Madrid, Spain
[5] Hosp Univ 12 Octubre, Serv Nefrol, Madrid, Spain
[6] CIBER CV, IdiPAZ Inst Hlth Res, Ctr Invest Biomed Red Enfermedades Cardiovasc, Madrid, Spain
[7] Inst Ramon y Cajal Invest Sanitaria IRyCis, Madrid, Spain
[8] Hosp Univ 12 Octubre, CIBER CV, Madrid, Spain
[9] European Univ Madrid, Sch Doctoral Studies & Res, Madrid, Spain
[10] Univ Autonoma Madrid, Fac Med, Dept Fisiol, Madrid, Spain
[11] Hosp Univ 12 Octubre, Inst Res Imas12, Cardiorenal Translat Lab, Res Ctr,Lab 2, Ave Cordoba S-N, Madrid 28041, Spain
[12] Fac Med, Arcobispo Morcillo 4, Madrid 28029, Spain
来源
JOURNAL OF PATHOLOGY | 2023年 / 261卷 / 04期
关键词
cardiorenal syndrome; TWEAK-Fn14; pathway; acute kidney injury; renal ischaemia/reperfusion; cardiomyocyte; calcium mishandling; CARDIOVASCULAR EVENTS; ACTIVATION; GROWTH; CARDIOMYOCYTE; CONTRACTION; INSULIN; FN14;
D O I
10.1002/path.6200
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 (SERCA(2a)) and ryanodine receptor (RyR(2)) function. Administration of anti-TWEAK antibody after reperfusion significantly improved alterations in Ca2+ cycling and arrhythmogenic events and prevented SERCA(2a )and RyR(2) 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.(c) 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
引用
收藏
页码:427 / 441
页数:15
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