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 (Ca 2+ ) 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 Ca 2+ handling and arrhythmogenic Ca 2+ events through an impairment in sarcoplasmic reticulum Ca 2+ ‐adenosine triphosphatase 2a pump (SERCA 2a ) and ryanodine receptor (RyR 2 ) function. Administration of anti‐TWEAK antibody after reperfusion significantly improved alterations in Ca 2+ 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 Ca 2+ mishandling inducer in cardiomyocytes, and highlights the cardioprotective benefits of TWEAK targeting in CRS3.