Evidence for a regulated Ca2+ entry in proximal tubular cells and its implication in calcium stone formation

Calcium phosphate (CaP) crystals, which begin to form in the early segments of the loop of Henle (LOH), are known to act as precursors for calcium stone formation. Proximal tubule (PT), just upstream to LOH, a major site for Ca 2+ reabsorption, could be a regulator to such CaP crystal formation. However, PT Ca 2+ reabsorption is mostly described as paracellular. Here we show the existence of a regulated transcellular Ca 2+ entry pathway in luminal membrane PT cells induced by Ca 2+ -sensing receptor (CSR) activation of transient receptor potential canonical 3 (TRPC3). In support, we found that both CSR and TRPC3 are physically and functionally coupled at the luminal membrane of PT cells. More importantly, TRPC3 deficient mice presented with a deficiency in PT Ca 2+ entry/transport, elevated urinary [Ca 2+ ], microcalcifications in LOH, and urine microcrystals formations. Together these data suggest that a signaling complex comprising of CSR and TRPC3 exists in the PT and can mediate transcellular Ca 2+ transport, which could be critical in maintaining the PT luminal [Ca 2+ ] to mitigate the CaP crystals in LOH and hence can hinder calcium stone formation.