HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 297/3/F720    most recent 00164.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Egbuna, O. Articles by Brown, E. PubMed PubMed Citation Articles by Egbuna, O. Articles by Brown, E.

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

¹Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston; ²Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston; ³Division of Nephrology, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; and ⁴Calcium Research Laboratory and Department of Medicine, McGill University Health Centre and McGill University, Montreal, Quebec, Canada

Submitted 19 March 2009 ; accepted in final form 26 May 2009

1,25(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.

vitamin D; kidney