Mechanism Underlying the Responsiveness to the Extracellular Phosphate and the Factors which Influence the Sensitivity to FGF23

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Phosphorus is a critical element involved in various biological processes, and organisms possess a system for its homeostasis. However, the mechanism for sensing the excess or shortage of phosphate remains unclear. In this study, we examined the responsiveness of the kidney-derived cell line to extracellular phosphate, and found that increased extracellular phosphate induced the activation of Raf/MEK/ERK pathway leading to altered gene expression. In addition, we revealed that the type III sodium/phosphate co-transporter PiT-1 as well as FGF receptor were involved in the responsiveness of the cells to increased extracellular phosphate. Signaling triggered by an increase in extracellular phosphate shared the same downstream cascade as FGF23 signaling, suggesting that extracellular phosphate itself might influence the sensitivity to FGF23. In conditions with abnormal levels of serum phosphate such as chronic kidney disease, the responsiveness of renal tubules to FGF23 might be altered.