Fibroblast growth factor 23 and fibroblast growth factor receptor 4 promote cardiac metabolic remodeling in chronic kidney disease Michaela A. A. Fuchs Emily J. Burke Nejla Latic Susan L. Murray Hanjun Li Matthew A Sparks Dennis Abraham Hengtao Zhang Paul Rosenberg Umber Saleem Arne Hansen Sara E. Miller Davis Ferreira Sonja Hänzelmann Fabian Hausmann Tobias Huber Reinhold G. Erben Kelsey Fisher-Wellman Nenad Bursac Myles Wolf Alexander Grabner Animals Renal Insufficiency, Chronic Complications Renal Insufficiency, Chronic Metabolism Renal Insufficiency, Chronic Pathology Renal Insufficiency, Chronic Chemically Induced Fibroblast Growth Factors Metabolism Myocytes, Cardiac Metabolism Myocytes, Cardiac Pathology Fibroblast Growth Factor-23 Hypertrophy, Left Ventricular Etiology Hypertrophy, Left Ventricular Metabolism Hypertrophy, Left Ventricular Pathology Receptor, Fibroblast Growth Factor, Type 4 Metabolism Receptor, Fibroblast Growth Factor, Type 4 Genetics Receptor, Fibroblast Growth Factor, Type 4 Deficiency Disease Models, Animal Rats Male Mitochondria, Heart Metabolism Mitochondria, Heart Pathology Mitochondria, Heart Ultrastructure Mice Mice, Inbred C57BL Ventricular Remodeling Mice, Knockout Glycolysis Signal Transduction Cells, Cultured Adenine Energy Metabolism Text journal article Testo Articolo di rivista application/pdf eng Elsevier Text Wissenschaftlicher Artikel http://creativecommons.org/licenses/by/4.0/ 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. 2025 Kidney International Copyright © 2025 International Society of Nephrology open access doi:10.1016/j.kint.2025.01.024 https://phaidra.vetmeduni.ac.at/o:4136