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
Institute of Anatomy, University of Zurich, Zurich, Switzerland; Swiss National Centre of Competence in Research "Kidney Control of Homeostasis", Zurich, Switzerland.
Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea.
J Biol Chem. 2024 Jan;300(1):105480. doi: 10.1016/j.jbc.2023.105480. Epub 2023 Nov 21.
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, 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 versus 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.
骨源性激素成纤维细胞生长因子23（FGF23）因其与慢性肾脏病和心血管疾病进展的关联，近来备受关注。细胞外钠浓度（[Na]）在骨代谢中起重要作用。低钠血症（血清[Na]降低）近来已被证明与慢性收缩性心力衰竭患者的FGF23水平独立相关。然而，关于[Na]对FGF23产生的直接影响却一无所知。在此，我们表明升高的[Na]（+20 mM）会抑制FGF23的形成，而低[Na]（-20 mM）则会增加成骨样细胞系UMR-106和MC3T3-E1中FGF23的合成。当通过甘露醇而非尿素改变渗透压时，观察到FGF23丰度有类似的双向变化，提示张力在FGF23形成中起作用。此外，FGF23的这些变化与NFAT5（活化T细胞核因子5）的表达呈负相关，NFAT5是负责张力介导的细胞适应的转录因子。此外，常导致低钠血症的精氨酸加压素并不影响FGF23的产生。接下来，我们对暴露于低[Na]和高[Na]的UMR-106细胞进行了全面且无偏倚的RNA测序分析，结果揭示了几个参与细胞对改变的张力适应的新基因。对经Crisp-Cas9介导的NFAT5缺失的细胞进行的进一步分析表明，NFAT5控制着众多与FGF23合成相关的基因，从而证实了其在[Na]介导的FGF23调节中的作用。与这些体外观察结果一致，我们发现低钠血症患者的FGF23水平较高。我们的结果表明，[Na]是FGF23合成的关键调节因子。
