Extracellular sodium regulates fibroblast growth factor 23 (FGF23) formation.

Radvanyi, Zsuzsa; Yoo, Eun Jin; Kandasamy, Palanivel; Salas-Bastos, Adrian; Monnerat, Sophie; Refardt, Julie; Christ-Crain, Mirjam; Hayashi, Himeka; Kondo, Yasuhiko; Jantsch, Jonathan; Rubio-Aliaga, Isabel; Sommer, Lukas; Wagner, Carsten A; Hediger, Matthias A; Kwon, Hyug Moo; Loffing, Johannes; Pathare, Ganesh (2024). Extracellular sodium regulates fibroblast growth factor 23 (FGF23) formation. The journal of biological chemistry, 300(1), p. 105480. American Society for Biochemistry and Molecular Biology 10.1016/j.jbc.2023.105480

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The bone-derived hormone fibroblast growth factor-23 (FGF23) has recently received much attention due to its association with chronic kidney disease and cardiovascular disease progression. Extracellular sodium concentration ([Na+]) plays a significant role in bone metabolism. Hyponatremia (lower serum [Na+]) has recently been shown to be independently associated with FGF23 levels in patients with chronic systolic heart failure. However, nothing is known about the direct impact of [Na+] on FGF23 production. Here, we show that an elevated [Na+] (+20 mM) suppressed FGF23 formation, whereas low [Na+] (-20 mM) increased FGF23 synthesis in the osteoblast-like cell lines UMR-106 and MC3T3-E1. Similar bidirectional changes in FGF23 abundance were observed when osmolality was altered by mannitol but not by urea, suggesting a role of tonicity in FGF23 formation. Moreover, these changes in FGF23 were inversely proportional to the expression of NFAT5 (nuclear factor of activated T cells-5), a transcription factor responsible for tonicity-mediated cellular adaptations. Furthermore arginine vasopressin (AVP), which is often responsible for hyponatremia, did not affect FGF23 production. Next, we performed a comprehensive and unbiased RNA-seq analysis of UMR-106 cells exposed to low vs. high [Na+], which revealed several novel genes involved in cellular adaptation to altered tonicity. Additional analysis of cells with Crisp-Cas9 mediated NFAT5 deletion indicated that NFAT5 controls numerous genes associated with FGF23 synthesis, thereby confirming its role in [Na+]-mediated FGF23 regulation. In line with these in vitro observations, we found that hyponatremia patients have higher FGF23 levels. Our results suggest that [Na+] is a critical regulator of FGF23 synthesis.

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