The full-length calcium-sensing receptor dampens the calcemic response to 1α,25(OH)2 vitamin D3 in vivo independently of parathyroid hormone

Abstract

1α,25(OH)2 vitamin D3 [1,25(OH)2D3] increases serum Ca2+ concentration in vivo, an action counteracted by activation of the Ca2+-sensing receptor (CaSR), which decreases parathyroid hormone (PTH) secretion and increases renal Ca2+ excretion. Relatively little is known of the role the CaSR plays in this response through its potentially direct actions in kidney, gut, and bone independently of PTH. We report PTH-independent roles of the CaSR in modulating the response to exogenous 1,25(OH)2D3 in mice with targeted disruption of both the CaSR and PTH genes (C−P−) compared with that in mice with disruption of the PTH gene alone (C+P−) or wild-type mice (C+P+). After intraperitoneal injection of 0.5 ng/g body wt 1,25(OH)2D3, peak calcemic responses were observed at 24 h in all three genotypes in association with 1) a greater increase in serum Ca2+ in C−P− mice than in the other genotypes on a Ca2+-replete diet that was attenuated by a Ca2+-deficient diet and pamidronate, 2) increased urinary Ca2+-to-creatinine ratios (UCa/Cr) in the C+P− and C+P+ mice but a lowered ratio in the C−P− mice on a Ca2+-replete diet, and 3) no increase in calcitonin (CT) secretion in the C+P+ and C+P− mice and a small increase in the C−P− mice. PTH deficiency had the anticipated effects on the expression of key genes involved in Ca2+ transport at baseline in the duodenum and kidney, and injection of 1,25(OH)2D3 increased gene expression 8 h later. However, the changes in the genes evaluated did not fully explain the differences in serum Ca2+ seen among the genotypes. In conclusion, mice lacking the full-length CaSR have increased sensitivity to the calcemic action of 1,25(OH)2D3 in the setting of PTH deficiency. This is principally from enhanced 1,25(OH)2D3-mediated gut Ca2+ absorption and decreased renal Ca2+ excretion, without any differences in bone-related release of Ca2+ or CT secretion among the three genotypes that could explain the differences in their calcemic responses.