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. 2023 Dec;261(4):427-441.
doi: 10.1002/path.6200. Epub 2023 Sep 30.

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

Jonay Poveda  1 , Laura González-Lafuente #  1 , Sara Vázquez-Sánchez #  1 , Elisa Mercado-García  1 , Elena Rodríguez-Sánchez  1 , Inés García-Consuegra  2 , Ana Belén Sanz  3 , Julián Segura  1   4 , María Fernández-Velasco  5 , Fernando Liaño  6 , Luis M Ruilope  1   7   8 , Gema Ruiz-Hurtado  1   7   9
Affiliations

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

Jonay Poveda et al. J Pathol. 2023 Dec.

Abstract

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. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Keywords: TWEAK-Fn14 pathway; acute kidney injury; calcium mishandling; cardiomyocyte; cardiorenal syndrome; renal ischaemia/reperfusion.

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References

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