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

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.

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Publication Details

Journal
Kidney International
Published
2025-02-07
DOI
https://doi.org/10.1016/j.kint.2025.01.024
Citations
23
Primary Topic
Parathyroid Disorders and Treatments
Type
article
Field-Weighted Citation Impact
32.91

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article

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

Sonja Hänzelmann, Myles Wolf, Umber Saleem, Dennis Abraham et al.
23 citations
Kidney International
Parathyroid Disorders and Treatments
32.91
article

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

Sonja Hänzelmann, Myles Wolf, Umber Saleem, Dennis Abraham, Nejla Latic, Nenad Bursac, Kelsey H. Fisher‐Wellman, Sara Miller, Fabian Hausmann, Reinhold G. Erben, Davis Ferreira, Emily J. Burke, Alexander Grabner, Hanjun Li, Matthew A. Sparks, Tobias B. Huber, Paul B. Rosenberg, Michaela Fuchs, Hengtao Zhang, Susan Murray, Arne Hansen
article en
23 citations

Abstract

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.

Kidney InternationalVol. 107(5)
Universität Hamburg (DE), Duke University (US), East Carolina University (US), Cornell University (US), Hanusch Hospital (AT), University Medical Center Hamburg-Eppendorf (DE), German Centre for Cardiovascular Research (DE), Ludwig Boltzmann Institute of Osteology (AT), Duke University Hospital (US)
American Heart Association, American Society of Nephrology, Pfizer, AstraZeneca, Sanofi, Fresenius Medical Care North America, Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, Vifor Pharma, National Institutes of Health, Novartis Pharma
Good health and well-being
Openalex Percentile: Top 0%
Parathyroid Disorders and Treatments
32.91
DOIOpen Access PDFOpenAlex
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