Journal
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM
Volume 304, Issue 9, Pages E977-E989Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpendo.00489.2012
Keywords
vitamin D receptor; 1 alpha,25-dihydroxyvitamin D-3; 25-hydroxyvitamin D-3; 24-hydroxylase cytochrome P-450; Cyp24a1; 1 alpha-hydroxylase; Cyp27b1; transient receptor potential cation channel; subfamily V; member 6; TRPV6
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Funding
- Canadian Institutes for Health Research
- National Sciences and the Engineering Research Council of Canada
- Alexander Graham Bell Canada Graduate Scholarship (NSERC-CGS)
- NSERC-CGS fellowship
- Ontario Graduate Scholarship (OGS) fellowship
- University of Toronto Open Fellowship
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The vitamin D receptor (VDR) maintains a balance of plasma calcium and 1 alpha,25-dihydroxyvitamin D-3 [1,25(OH)(2)D-3], its natural active ligand, by directly regulating the calcium ion channel (TRPV6) and degradation enzyme (CYP24A1), and indirectly regulating the parathyroid hormone (PTH) for feedback regulation of the synthetic enzyme CYP27B1. Studies that examined the intricate relationships between plasma and tissue 1,25(OH)(2)D-3 levels and changes in VDR target genes and plasma calcium and PTH are virtually nonexistent. In this study, we investigated temporal correlations between tissue 1,25(OH)(2)D-3 concentrations and VDR target genes in ileum and kidney and plasma calcium and PTH concentrations in response to 1,25(OH)(2)D-3 treatment in mice (2.5 mu g/kg ip, singly or q2d x 4). After a single ip dose, plasma 1,25(OH)(2)D-3 peaked at similar to 0.5 h and then decayed biexponentially, falling below basal levels after 24 h and then returning to baseline after 8 days. Upon repetitive ip dosing, plasma, ileal, renal, and bone 1,25(OH)(2)D-3 concentrations rose and decayed in unison. Temporal profiles showed increased expressions of ileal Cyp24a1 and renal Cyp24a1, Mdr1/P-gp, and VDR but decreased renal Cyp27b1 mRNA after a time delay in VDR activation. Increased plasma calcium and attenuated PTH levels and increased ileal and renal Trpv6 expression paralleled the changes in tissue 1,25(OH) 2D3 concentrations. Gene changes in the kidney were more sustained than those in intestine, but the magnitudes of change for Cyp24a1 and Trpv6 were lower than those in intestine. The data revealed that 1,25(OH)(2)D-3 equilibrates with tissues rapidly, and VDR target genes respond quickly to exogenously administered 1,25(OH)(2)D-3.
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