Cardiorenal Translational Laboratory, Institute of Research Imas12, Hospital Universitario 12 de Octubre, Madrid, Spain.
Proteomics Unit, Institute of Research Imas12, Hospital Universitario 12 de Octubre, Madrid, Spain.
J Pathol. 2023 Dec;261(4):427-441. doi: 10.1002/path.6200. Epub 2023 Sep 30.
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 ) 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 handling and arrhythmogenic Ca events through an impairment in sarcoplasmic reticulum Ca -adenosine triphosphatase 2a pump (SERCA ) and ryanodine receptor (RyR ) function. Administration of anti-TWEAK antibody after reperfusion significantly improved alterations in Ca cycling and arrhythmogenic events and prevented SERCA and RyR 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 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.
心脏和肾脏有着密切相关的病理生理学。急性肾损伤（AKI）与心血管事件发生率显著增加相关，这种关系被定义为 3 型心肾综合征（CRS3）。然而，触发心脏病的潜在机制仍不清楚，特别是 AKI 对心脏结局和总体死亡率的临床影响。肿瘤坏死因子样凋亡弱诱导剂（TWEAK）及其受体成纤维细胞生长因子诱导 14（Fn14）独立参与了心脏和肾脏衰竭的发病机制，最近的研究提出 TWEAK 可能是一种治疗靶点；然而，它在与 CRS3 相关的心脏损伤中的具体作用仍有待阐明。首先，我们在一项回顾性纵向临床研究中表明，可溶性 TWEAK 血浆水平是 AKI 患者死亡的预测生物标志物。此外，外源性 TWEAK 应用于原代心室肌细胞诱导了相关的钙（Ca ）处理改变。接下来，我们研究了 TWEAK-Fn14 轴在小鼠肾缺血再灌注（I/R）损伤后心肌细胞功能中的作用。我们观察到，TWEAK-Fn14 信号在 AKI 小鼠的心脏中被激活。小鼠的心肌细胞内 Ca 处理也发生了明显改变，心律失常性 Ca 事件通过肌浆网 Ca -三磷酸腺苷酶 2a 泵（SERCA）和兰尼碱受体（RyR）功能障碍而发生。再灌注后给予抗 TWEAK 抗体可显著改善 Ca 循环和心律失常性事件的改变，并防止 SERCA 和 RyR 的改变。总之，这项研究确立了 TWEAK-Fn14 途径在与 CRS3 相关的心脏功能障碍中的相关性，既作为 AKI 患者死亡率的预测因子，又作为心肌细胞中 Ca 处理紊乱的诱导剂，并强调了 TWEAK 靶向在 CRS3 中的心脏保护作用。
