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

doi:10.1016/j.kint.2025.01.024

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Title (eng)

Fibroblast growth factor 23 and fibroblast growth factor receptor 4 promote cardiac metabolic remodeling in chronic kidney disease

Author

Michaela A. A. Fuchs

Emily J. Burke

Nejla Latic

University of Veterinary Medicine Vienna

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

Abstract (eng)

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.

Keywords (eng)

AnimalsRenal Insufficiency, Chronic ComplicationsRenal Insufficiency, Chronic MetabolismRenal Insufficiency, Chronic PathologyRenal Insufficiency, Chronic Chemically InducedFibroblast Growth Factors MetabolismMyocytes, Cardiac MetabolismMyocytes, Cardiac PathologyFibroblast Growth Factor-23Hypertrophy, Left Ventricular EtiologyHypertrophy, Left Ventricular MetabolismHypertrophy, Left Ventricular PathologyReceptor, Fibroblast Growth Factor, Type 4 MetabolismReceptor, Fibroblast Growth Factor, Type 4 GeneticsReceptor, Fibroblast Growth Factor, Type 4 DeficiencyDisease Models, AnimalRatsMaleMitochondria, Heart MetabolismMitochondria, Heart PathologyMitochondria, Heart UltrastructureMiceMice, Inbred C57BLVentricular RemodelingMice, KnockoutGlycolysisSignal TransductionCells, CulturedAdenineEnergy Metabolism

Type (eng)

journal article

Language

[eng]

Persistent identifier

https://phaidra.vetmeduni.ac.at/o:4136

DOI

10.1016/j.kint.2025.01.024

Is in series

Title (eng)

Kidney International

Volume