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Cardiac Fibroblast Growth Factor 23 Excess Does Not Induce Left Ventricular Hypertrophy in Healthy Mice
Maren Leifheit-Nestler1, Miriam A Wagner1, Beatrice Richter1
1Department of Pediatric Kidney, Liver and Metabolic Diseases, Pediatric Research Center, Hannover Medical School, Hanover, Germany.
Insights
Elevated fibroblast growth factor 23 (FGF23) from the heart does not cause left ventricular hypertrophy (LVH) in healthy mice. The presence of klotho prevents FGF23 from inducing cardiac damage.
Area of Science:
- Cardiovascular Biology
- Endocrinology
- Nephrology
Background:
- Fibroblast growth factor 23 (FGF23) is elevated in chronic kidney disease (CKD) and linked to left ventricular hypertrophy (LVH).
- FGF23-induced LVH is thought to occur via klotho-independent pathways, but its direct cardiotoxic effects in healthy individuals are unclear.
Purpose of the Study:
- To investigate whether increased cardiac FGF23 synthesis causes cardiac remodeling and dysfunction in healthy mice.
- To determine if FGF23 directly induces LVH independent of kidney disease or systemic alterations.
Main Methods:
- Generated a mouse model with cardiac-specific FGF23 overexpression using adeno-associated virus (AAV-Fgf23).
- Assessed cardiac structure, function, and molecular signaling pathways.
- Utilized in vitro studies with neonatal rat ventricular myocytes (NRVM) to evaluate FGF23 effects on cardiac cells.
Main Results:
- AAV-Fgf23 mice exhibited elevated cardiac and circulating FGF23 levels, confirming cardiac origin.
- Cardiac-derived FGF23 activated renal FGF23-related signaling pathways, impacting phosphate and vitamin D metabolism.
- No LVH, fibrosis, or impaired cardiac function was observed in AAV-Fgf23 mice; klotho co-administration prevented FGF23-induced myocyte hypertrophy in vitro.
Conclusions:
- Chronic elevation of cardiac FGF23 does not induce LVH or cardiac dysfunction in healthy mice.
- The physiological presence of klotho is crucial in preventing FGF23-mediated cardiotoxicity.
- FGF23 excess alone, without underlying CKD pathology, does not appear to be directly cardiotoxic.
Abstract:
Fibroblast growth factor (FGF) 23 is elevated in chronic kidney disease (CKD) to maintain phosphate homeostasis. FGF23 is associated with left ventricular hypertrophy (LVH) in CKD and induces LVH via klotho-independent FGFR4-mediated activation of calcineurin/nuclear factor of activated T cells (NFAT) signaling in animal models, displaying systemic alterations possibly contributing to heart injury. Whether elevated FGF23 per se causes LVH in healthy animals is unknown. By generating a mouse model with high intra-cardiac Fgf23 synthesis using an adeno-associated virus (AAV) expressing murine Fgf23 (AAV-Fgf23) under the control of the cardiac troponin T promoter, we investigated how cardiac Fgf23 affects cardiac remodeling and function in C57BL/6 wild-type mice. We report that AAV-Fgf23 mice showed increased cardiac-specific Fgf23 mRNA expression and synthesis of full-length intact Fgf23 (iFgf23) protein. Circulating total and iFgf23 levels were significantly elevated in AAV-Fgf23 mice compared to controls with no difference in bone Fgf23 expression, suggesting a cardiac origin. Serum of AAV-Fgf23 mice stimulated hypertrophic growth of neonatal rat ventricular myocytes (NRVM) and induced pro-hypertrophic NFAT target genes in klotho-free culture conditions in vitro. Further analysis revealed that renal Fgfr1/klotho/extracellular signal-regulated kinases 1/2 signaling was activated in AAV-Fgf23 mice, resulting in downregulation of sodium-phosphate cotransporter NaPi2a and NaPi2c and suppression of Cyp27b1, further supporting the bioactivity of cardiac-derived iFgf23. Of interest, no LVH, LV fibrosis, or impaired cardiac function was observed in klotho sufficient AAV-Fgf23 mice. Verified in NRVM, we show that co-stimulation with soluble klotho prevented Fgf23-induced cellular hypertrophy, supporting the hypothesis that high cardiac Fgf23 does not act cardiotoxic in the presence of its physiological cofactor klotho. In conclusion, chronic exposure to elevated cardiac iFgf23 does not induce LVH in healthy mice, suggesting that Fgf23 excess per se does not tackle the heart.
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