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

Author(s):  
Maren Leifheit-Nestler ◽  
Miriam A. Wagner ◽  
Beatrice Richter ◽  
Corinna Piepert ◽  
Fiona Eitner ◽  
...  

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.

2021 ◽  
Vol 9 ◽  
Author(s):  
Andrea Grund ◽  
Manish D. Sinha ◽  
Dieter Haffner ◽  
Maren Leifheit-Nestler

Cardiovascular diseases (CVD) are a hallmark in pediatric patients with chronic kidney disease (CKD) contributing to an enhanced risk of all-cause and CV morbidity and mortality in these patients. The bone-derived phosphaturic hormone fibroblast growth factor (FGF) 23 progressively rises with declining kidney function to maintain phosphate homeostasis, with up to 1,000-fold increase in patients with kidney failure requiring dialysis. FGF23 is associated with the development of left ventricular hypertrophy (LVH) and thereby accounts to be a CVD risk factor in CKD. Experimentally, FGF23 directly induces hypertrophic growth of cardiac myocytes in vitro and LVH in vivo. Further, clinical studies in adult CKD have observed cardiotoxicity associated with FGF23. Data regarding prevalence and determinants of FGF23 excess in children with CKD are limited. This review summarizes current data and discusses whether FGF23 may be a key driver of LVH in pediatric CKD.


2012 ◽  
Vol 27 (11) ◽  
pp. 2129-2136 ◽  
Author(s):  
Wacharee Seeherunvong ◽  
Carolyn L. Abitbol ◽  
Jayanthi Chandar ◽  
Paolo Rusconi ◽  
Gaston E. Zilleruelo ◽  
...  

2013 ◽  
Vol 61 (1) ◽  
pp. 67-73 ◽  
Author(s):  
Kelsey Smith ◽  
Christopher deFilippi ◽  
Tamara Isakova ◽  
Orlando M. Gutiérrez ◽  
Karen Laliberte ◽  
...  

2016 ◽  
Vol 85 (2016) (03) ◽  
pp. 135-141 ◽  
Author(s):  
Margarida Sarmento-Dias ◽  
Carla Santos-Araújo ◽  
Rui Poínhos ◽  
Bruno Oliveira ◽  
Isabell Soares Silva ◽  
...  

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