Cardiac Fibroblast Growth Factor 23 Excess Does Not Induce Left Ventricular Hypertrophy in Healthy Mice

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.

The Role of Oncostatin M and Its Receptor Complexes in Cardiomyocyte Protection, Regeneration, and Failure

“…To distinguish an OSMRmediated effect from other IL-6 receptor complexes, one must look for more specific effects of this cytokine. ANP and BNP are regarded as biomarkers for cardiac remodeling induced by various cardioactive agents including FGF2, but only the increasingly recognized cardiac remodeling marker FGF-23 appears to be specific to cardiac OSM activity [11,17,[138][139][140]. Other strong indicators of fetal remodeling are non-muscle α-actinins (Actn1 and Actn4), which are expressed during the early postnatal weeks in the normal human myocardium but are barely detectable in adult cardiomyocytes [116].…”

Chronic kidney disease associated cardiomyopathy: recent advances and future perspectives

“…Markedly increased concentrations of the phosphaturic hormone Fibroblast Growth Factor 23 (FGF23), and decreased concentrations of the soluble FGF23 co-receptor, a-klotho, are observed in CKD, and associated with higher rates of LVH, heart failure, cardiovascular and all-cause mortality [34][35][36][37][38][39][40]. The hypertrophic remodeling effect of FGF23 on cardiac myocytes has been demonstrated in certain animal models of CKD [35], but not replicated by others [38].…”

Updates in the chronic kidney disease-mineral bone disorder show the role of osteocytic proteins, a potential mechanism of the bone—Vascular paradox, a therapeutic target, and a biomarker

“…It appears that the function of FGF23/FGFR4 is dependent on the co-receptor. When co-receptor function is served by heparin sulfate, myocyte hypertrophy is stimulated through activation of NFATC1, but if klotho serves as the co-receptor, hypertrophy is not stimulated ( Leifheit-Nestler et al, 2021 ).…”