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 (CP) 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 CP 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 CP 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 CP 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.

  • vitamin D
  • kidney
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