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Abstract: TH-OR87

CKD Causes Cardiac Metabolic Remodeling via FGF23 and FGFR4

Session Information

Category: Hypertension and CVD

  • 1601 Hypertension and CVD: Basic


  • Fuchs, Michaela A.A., Duke University School of Medicine, Durham, North Carolina, United States
  • Burke, Emily, Duke University School of Medicine, Durham, North Carolina, United States
  • Wolf, Myles, Duke University School of Medicine, Durham, North Carolina, United States
  • Grabner, Alexander, Duke University School of Medicine, Durham, United States

In chronic kidney disease (CKD), serum levels of fibroblast growth factor (FGF) 23 are associated with increased risks of left ventricular hypertrophy (LVH), heart failure and death. We reported that FGF23 directly induces hypertrophic growth of cultured cardiomyocytes and structural cardiac remodeling in rodents via cardiac FGF receptor (FGFR) 4. Mitochondrial dysfunction and cardiac metabolic remodeling contribute to the development and progression of LVH and heart failure. We tested the hypothesis that FGF23-FGFR4 promote cardiac metabolic remodeling in CKD.


We induced CKD in FGFR4 global knock out mice, mice with inducible cardiomyocyte-specific deletion of FGFR4 and wildtype littermates using a 0.2% adenine diet for 16 weeks. At study end, cardiac structure, function, metabolism and mitochondrial composition and function was analyzed. In neonatal rat ventricular myocytes and bioengineered cardio-bundles we studied mitochondrial respiration, substrate utilization and cellular hypertrophy in response to FGF23 and inhibition of FGFR4.


CKD induced robust changes to the cardiac mitoproteome (118 of 781 proteins significantly regulated) and impairs cardiac metabolism with significant alterations in cardiac organic acids, amino acids and acylcarnitines as well as mitochondrial respiration through complex I and II. Alterations in the cardiac metabolome preceded overt signs of structural cardiac remodeling and heart failure. In mice, deletion of FGFR4 prevented cardiac metabolic remodeling, mitochondrial dysfunction and heart failure in CKD. In cardio-bundles, FGF23 transcriptionally regulated metabolism. In cultured cardiomyocytes, FGF23 impaired mitochondrial respiration and substrate utilization via FGFR4, characterized by increased proton leak (fold change ctrl vs. FGF23: 1 ± 0.48 vs 1.43 ± 0.56*) and elevated glycolysis (fold change ctrl vs. FGF23: 1 ± 0.46 vs. 1.52 ± 0.66*; *=p<0.05).


Cardiac metabolic remodeling is an early complication of CKD that contributes to LVH. Mechanistically, FGF23-mediated activation of FGFR4 causes mitochondrial dysfunction including impaired respiration and increased glycolysis. We postulate that early pharmacologic inhibition of FGFR4 might serve as novel therapeutic intervention to attenuate heart failure in patients with CKD.