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, 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 (RyR₂) function. Administration of anti-TWEAK antibody after reperfusion significantly improved alterations in Ca²⁺ cycling and arrhythmogenic events and prevented SERCA_2a 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.