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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\nmetabolic 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."}]}],"bf:provisionActivity":[{"@type":"bf:Publication","bf:agent":[{"@type":"schema:Organization","schema:name":[{"@value":"Elsevier"}]}]}],"dce:rights":[{"@language":"eng","@value":"Copyright © 2025 International Society of Nephrology"}],"dce:subject":[{"@type":"skos:Concept","skos:prefLabel":[{"@language":"eng","@value":"Animals"}]},{"@type":"skos:Concept","skos:prefLabel":[{"@language":"eng","@value":"Renal Insufficiency, Chronic Complications"}]},{"@type":"skos:Concept","skos:prefLabel":[{"@language":"eng","@value":"Renal Insufficiency, Chronic Metabolism"}]},{"@type":"skos:Concept","skos:prefLabel":[{"@language":"eng","@value":"Renal Insufficiency, Chronic 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