Fuchs Michaela A A, Burke Emily J, Latic Nejla, Murray Susan L, Li Hanjun, Sparks Matthew A, Abraham Dennis, Zhang Hengtao, Rosenberg Paul, Saleem Umber, Hansen Arne, Miller Sara E, Ferreira Davis, Hänzelmann Sonja, Hausmann Fabian, Huber Tobias, Erben Reinhold G, Fisher-Wellman Kelsey, Bursac Nenad, Wolf Myles, Grabner Alexander
Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA.
Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA; Department of Biomedical Sciences, University of Veterinary Medicine, Vienna, Austria.
Kidney Int. 2025 May;107(5):852-868. doi: 10.1016/j.kint.2025.01.024. Epub 2025 Feb 7.
Chronic kidney disease (CKD) is a global health epidemic that greatly increases mortality due to cardiovascular disease. Left ventricular hypertrophy (LVH) is an important mechanism of cardiac injury in CKD. High serum levels of fibroblast growth factor (FGF) 23 in patients with CKD may contribute mechanistically to the pathogenesis of LVH by activating FGF receptor (FGFR) 4 signaling in cardiac myocytes. Mitochondrial dysfunction and cardiac metabolic remodeling are early features of cardiac injury that predate development of hypertrophy, but these mechanisms have been insufficiently studied in models of CKD. We found in wild-type mice with CKD induced by adenine diet, that morphological changes occurred in mitochondrial structure and cardiac mitochondrial and that metabolic dysfunction preceded the development of LVH. In bioengineered cardio-bundles and neonatal rat ventricular myocytes grown in vitro, FGF23-mediated activation of FGFR4 caused mitochondrial pathology, characterized by increased bioenergetic stress and increased glycolysis that preceded the development of cellular hypertrophy. The cardiac metabolic changes and associated mitochondrial alterations in mice with CKD were prevented by global and cardiac-specific deletion of FGFR4. Our findings indicate that metabolic remodeling and mitochondrial dysfunction are early cardiac complications of CKD that precede structural remodeling of the heart. Mechanistically, FGF23-mediated activation of FGFR4 causes mitochondrial dysfunction, suggesting that early pharmacologic inhibition of FGFR4 might serve as novel therapeutic intervention to prevent development of LVH and heart failure in patients with CKD.
慢性肾脏病（CKD）是一种全球性的健康流行病，它会大幅增加心血管疾病导致的死亡率。左心室肥厚（LVH）是CKD中心脏损伤的一个重要机制。CKD患者血清中高成纤维细胞生长因子（FGF）23水平可能通过激活心肌细胞中的FGF受体（FGFR）4信号通路，在LVH的发病机制中发挥作用。线粒体功能障碍和心脏代谢重塑是心脏损伤的早期特征，早于肥厚的发生，但在CKD模型中对这些机制的研究还不够充分。我们在通过腺嘌呤饮食诱导的CKD野生型小鼠中发现，线粒体结构以及心脏线粒体发生了形态学变化，并且代谢功能障碍先于LVH的发展。在体外培养的生物工程心脏束和新生大鼠心室肌细胞中，FGF23介导的FGFR4激活导致线粒体病变，其特征是在细胞肥大发展之前生物能应激增加和糖酵解增加。通过全局和心脏特异性敲除FGFR4，可预防CKD小鼠的心脏代谢变化和相关的线粒体改变。我们的研究结果表明，代谢重塑和线粒体功能障碍是CKD早期的心脏并发症，先于心脏的结构重塑。从机制上讲，FGF23介导的FGFR4激活导致线粒体功能障碍，这表明早期对FGFR4进行药物抑制可能作为一种新的治疗干预措施，以预防CKD患者LVH和心力衰竭的发生。
