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Fibroblast Growth Factor (FGF) 23 and FGF Receptor 4 promote cardiac metabolic remodeling in chronic kidney disease.

Publication ,  Journal Article
Fuchs, MA; Burke, EJ; Latic, N; Murray, S; Li, H; Sparks, M; Abraham, D; Zhang, H; Rosenberg, P; Hänzelmann, S; Hausmann, F; Huber, T ...
Published in: Res Sq
December 23, 2023

Chronic kidney disease (CKD) is a global health epidemic that significantly 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 of disease have been insufficiently studied in models of CKD. Wild-type mice with CKD induced by adenine diet developed LVH that was preceded by morphological changes in mitochondrial structure and evidence of cardiac mitochondrial and metabolic dysfunction. In bioengineered cardio-bundles and neonatal rat ventricular myocytes grown in vitro, FGF23-mediated activation of FGFR4 caused a 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 or cardiac-specific deletion of FGFR4. These findings indicate that metabolic remodeling and eventually 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.

Duke Scholars

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Res Sq

DOI

Publication Date

December 23, 2023

Location

United States
 

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Fuchs, M. A., Burke, E. J., Latic, N., Murray, S., Li, H., Sparks, M., … Grabner, A. (2023). Fibroblast Growth Factor (FGF) 23 and FGF Receptor 4 promote cardiac metabolic remodeling in chronic kidney disease. Res Sq. https://doi.org/10.21203/rs.3.rs-3705543/v1
Fuchs, Michaela A., Emily J. Burke, Nejla Latic, Susan Murray, Hanjun Li, Matthew Sparks, Dennis Abraham, et al. “Fibroblast Growth Factor (FGF) 23 and FGF Receptor 4 promote cardiac metabolic remodeling in chronic kidney disease.Res Sq, December 23, 2023. https://doi.org/10.21203/rs.3.rs-3705543/v1.
Fuchs MA, Burke EJ, Latic N, Murray S, Li H, Sparks M, et al. Fibroblast Growth Factor (FGF) 23 and FGF Receptor 4 promote cardiac metabolic remodeling in chronic kidney disease. Res Sq. 2023 Dec 23;
Fuchs, Michaela A., et al. “Fibroblast Growth Factor (FGF) 23 and FGF Receptor 4 promote cardiac metabolic remodeling in chronic kidney disease.Res Sq, Dec. 2023. Pubmed, doi:10.21203/rs.3.rs-3705543/v1.
Fuchs MA, Burke EJ, Latic N, Murray S, Li H, Sparks M, Abraham D, Zhang H, Rosenberg P, Hänzelmann S, Hausmann F, Huber T, Erben R, Fisher-Wellman K, Bursac N, Wolf M, Grabner A. Fibroblast Growth Factor (FGF) 23 and FGF Receptor 4 promote cardiac metabolic remodeling in chronic kidney disease. Res Sq. 2023 Dec 23;

Published In

Res Sq

DOI

Publication Date

December 23, 2023

Location

United States