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

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 (NFA...

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Autores principales: Leifheit-Nestler, Maren, Wagner, Miriam A., Richter, Beatrice, Piepert, Corinna, Eitner, Fiona, Böckmann, Ineke, Vogt, Isabel, Grund, Andrea, Hille, Susanne S., Foinquinos, Ariana, Zimmer, Karina, Thum, Thomas, Müller, Oliver J., Haffner, Dieter
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8581397/
https://www.ncbi.nlm.nih.gov/pubmed/34778257
http://dx.doi.org/10.3389/fcell.2021.745892
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author Leifheit-Nestler, Maren
Wagner, Miriam A.
Richter, Beatrice
Piepert, Corinna
Eitner, Fiona
Böckmann, Ineke
Vogt, Isabel
Grund, Andrea
Hille, Susanne S.
Foinquinos, Ariana
Zimmer, Karina
Thum, Thomas
Müller, Oliver J.
Haffner, Dieter
author_facet Leifheit-Nestler, Maren
Wagner, Miriam A.
Richter, Beatrice
Piepert, Corinna
Eitner, Fiona
Böckmann, Ineke
Vogt, Isabel
Grund, Andrea
Hille, Susanne S.
Foinquinos, Ariana
Zimmer, Karina
Thum, Thomas
Müller, Oliver J.
Haffner, Dieter
author_sort Leifheit-Nestler, Maren
collection PubMed
description 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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spelling pubmed-85813972021-11-12 Cardiac Fibroblast Growth Factor 23 Excess Does Not Induce Left Ventricular Hypertrophy in Healthy Mice Leifheit-Nestler, Maren Wagner, Miriam A. Richter, Beatrice Piepert, Corinna Eitner, Fiona Böckmann, Ineke Vogt, Isabel Grund, Andrea Hille, Susanne S. Foinquinos, Ariana Zimmer, Karina Thum, Thomas Müller, Oliver J. Haffner, Dieter Front Cell Dev Biol Cell and Developmental Biology 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. Frontiers Media S.A. 2021-10-28 /pmc/articles/PMC8581397/ /pubmed/34778257 http://dx.doi.org/10.3389/fcell.2021.745892 Text en Copyright © 2021 Leifheit-Nestler, Wagner, Richter, Piepert, Eitner, Böckmann, Vogt, Grund, Hille, Foinquinos, Zimmer, Thum, Müller and Haffner. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
Leifheit-Nestler, Maren
Wagner, Miriam A.
Richter, Beatrice
Piepert, Corinna
Eitner, Fiona
Böckmann, Ineke
Vogt, Isabel
Grund, Andrea
Hille, Susanne S.
Foinquinos, Ariana
Zimmer, Karina
Thum, Thomas
Müller, Oliver J.
Haffner, Dieter
Cardiac Fibroblast Growth Factor 23 Excess Does Not Induce Left Ventricular Hypertrophy in Healthy Mice
title Cardiac Fibroblast Growth Factor 23 Excess Does Not Induce Left Ventricular Hypertrophy in Healthy Mice
title_full Cardiac Fibroblast Growth Factor 23 Excess Does Not Induce Left Ventricular Hypertrophy in Healthy Mice
title_fullStr Cardiac Fibroblast Growth Factor 23 Excess Does Not Induce Left Ventricular Hypertrophy in Healthy Mice
title_full_unstemmed Cardiac Fibroblast Growth Factor 23 Excess Does Not Induce Left Ventricular Hypertrophy in Healthy Mice
title_short Cardiac Fibroblast Growth Factor 23 Excess Does Not Induce Left Ventricular Hypertrophy in Healthy Mice
title_sort cardiac fibroblast growth factor 23 excess does not induce left ventricular hypertrophy in healthy mice
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8581397/
https://www.ncbi.nlm.nih.gov/pubmed/34778257
http://dx.doi.org/10.3389/fcell.2021.745892
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