Dietary inorganic phosphate (Pi) intake triggers rapid adaptive responses in renal Pi handling, primarily through downregulation of the sodium-phosphate cotransporters NaPi-IIa and NaPi-IIc. While parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) are established regulators of this process, significant phosphaturia and transporter downregulation occur even in their absence, suggesting additional regulatory mechanisms. This study investigated the role of the calcium-sensing receptor (CaSR) in mediating the acute renal response to oral Pi loading.

The CaSR, which senses both calcium and phosphate, regulates PTH and FGF23 secretion and may directly influence renal Pi handling. Pharmacological modulation using the calcimimetic cinacalcet resulted in hyperphosphatemia, blunted PTH levels upon Pi administration, reduced Pi-induced phosphaturia, and abolished NaPi-IIa downregulation. Conversely, the calcilytic NPS-2143 exaggerated the PTH response but did not prevent NaPi-IIa downregulation. In mice with a dominant inactivating Casr mutation (CasrBCH002), baseline NaPi-IIa expression was elevated, yet transporter downregulation remained largely intact. Double CasrBCH002/PTH knockout animals showed only subtle differences in NaPi-IIa and NaPi-IIc downregulation compared to controls.

These findings demonstrate that acute modulation of CaSR activity significantly affects the endocrine and renal response to Pi loading, primarily through its regulation of PTH secretion. However, no evidence was found for a direct role of CaSR in renal Pi handling beyond its endocrine function. The data suggest that while CaSR is crucial for orchestrating the hormonal response to dietary Pi, additional unidentified signals must contribute to the acute adaptation of renal phosphate transporters independent of PTH, FGF23, and direct CaSR signaling.