Fibroblast growth factor 23 decreases PDE4 expression in heart increasing the risk of cardiac arrhythmia; Klotho opposes
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ORIGINAL CONTRIBUTION
Fibroblast growth factor 23 decreases PDE4 expression in heart increasing the risk of cardiac arrhythmia; Klotho opposes these effects Marta Lindner1 · Hind Mehel1 · Amandine David1 · Christine Leroy1 · Martine Burtin1 · Gérard Friedlander1,2,3 · Fabiola Terzi1 · Delphine Mika4 · Rodolphe Fischmeister4 · Dominique Prié1,2,5 Received: 1 April 2020 / Accepted: 1 July 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract The concentration of fibroblast growth factor 23 (FGF23) rises progressively in renal failure (RF). High FGF23 concentrations have been consistently associated with adverse cardiovascular outcomes or death, in chronic kidney disease (CKD), heart failure or liver cirrhosis. We identified the mechanisms whereby high concentrations of FGF23 can increase the risk of death of cardiovascular origin. We studied the effects of FGF23 and Klotho in adult rat ventricular cardiomyocytes (ARVMs) and on the heart of mice with CKD. We show that FGF23 increases the frequency of spontaneous calcium waves (SCWs), a marker of cardiomyocyte arrhythmogenicity, in ARVMs. FGF23 increased sarcoplasmic reticulum C a2+ leakage, basal 2+ phosphorylation of Ca -cycling proteins including phospholamban and ryanodine receptor type 2. These effects are secondary to a decrease in phosphodiesterase 4B (PDE4B) in ARVMs and in heart of mice with RF. Soluble Klotho, a circulating form of the FGF23 receptor, prevents FGF23 effects on ARVMs by increasing PDE3A and PDE3B expression. Our results suggest that the combination of high FGF23 and low sKlotho concentrations decreases PDE activity in ARVMs, which favors the occurrence of ventricular arrhythmias and may participate in the high death rate observed in patients with CKD. Keywords Fibroblast growth factor 23 · Klotho · Heart · Phosphodiesterases · Arrhythmia · Renal failure
Introduction Fibroblast growth factor 23 (FGF23) is a hormone synthesized by osteoblasts and osteocytes. Its physiological role is to maintain phosphate and calcitriol concentrations within Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00395-020-0810-6) contains supplementary material, which is available to authorized users. * Dominique Prié [email protected] 1
INSERM U1151-CNRS UMR8253, Paris, France
2
Université de Paris Faculté de Médecine, Paris, France
3
Service de Physiologie Explorations Fonctionnelles Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France
4
Université Paris-Saclay, Inserm U1180, 92296 Châtenay‑Malabry, France
5
Service de Physiologie Explorations Fonctionnelles Hôpital Necker‑Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France
the normal range. Under physiological conditions, the main target of FGF23 is the kidney. FGF23 increases phosphate excretion in urine by inhibiting the activity of the renal sodium–phosphate co-transporters [9]. FGF23 lowers calcitriol concentration by diminishing its synthesis, and by st
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