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Suppression of Pro-fibrotic Signaling Potentiates Factor-mediated Reprogramming of Mouse Embryonic Fibroblasts into Induced Cardiomyocytes
Published on: June 3, 2018
Fibroblast Growth Factor (FGF) 23 and FGF Receptor 4 promote cardiac metabolic remodeling in chronic kidney disease
Michaela A Fuchs1, Emily J Burke1, Nejla Latic1,2
1Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA.
Insights
Chronic kidney disease (CKD) causes heart problems like left ventricular hypertrophy (LVH). Blocking FGF receptor 4 may prevent cardiac damage in CKD patients.
Area of Science:
- Nephrology
- Cardiology
- Mitochondrial Biology
Background:
- Chronic kidney disease (CKD) is a global health issue linked to increased cardiovascular mortality.
- Left ventricular hypertrophy (LVH) is a key cardiac injury mechanism in CKD.
- High fibroblast growth factor (FGF) 23 levels in CKD may drive LVH via FGF receptor (FGFR) 4 signaling.
Approach:
- Investigated CKD-induced LVH in mice using an adenine diet.
- Examined mitochondrial structure, function, and metabolic remodeling in cardiac tissue.
- Utilized in vitro models (cardio-bundles, neonatal rat ventricular myocytes) to study FGF23/FGFR4 effects.
- Assessed the impact of FGFR4 deletion on cardiac changes in CKD mice.
Key Points:
- CKD mice developed LVH preceded by mitochondrial morphological changes and metabolic dysfunction.
- FGF23 activation of FGFR4 in vitro induced mitochondrial pathology and metabolic stress before hypertrophy.
- Global or cardiac-specific FGFR4 deletion prevented CKD-related cardiac metabolic and mitochondrial alterations.
- Metabolic remodeling and mitochondrial dysfunction are early cardiac events in CKD, preceding structural changes.
Conclusions:
- FGF23-mediated FGFR4 activation drives mitochondrial dysfunction and metabolic remodeling in the CKD heart.
- These early cardiac changes precede the development of left ventricular hypertrophy.
- Targeting FGFR4 early in CKD could be a novel therapeutic strategy to prevent LVH and heart failure.
Abstract:
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.
