Dr DeLuca is CEO of Deltanoid Pharmaceuticals and served as a consultant for Abbott Laboratories and Pfizer. All other authors have no conflict of interest.
Mechanism and Function of High Vitamin D Receptor Levels in Genetic Hypercalciuric Stone-Forming Rats
Version of Record online: 29 NOV 2004
Copyright © 2005 ASBMR
Journal of Bone and Mineral Research
Volume 20, Issue 3, pages 447–454, March 2005
How to Cite
Karnauskas, A. J., van Leeuwen, J. P., van den Bemd, G.-J. C., Kathpalia, P. P., DeLuca, H. F., Bushinsky, D. A. and Favus, M. J. (2005), Mechanism and Function of High Vitamin D Receptor Levels in Genetic Hypercalciuric Stone-Forming Rats. J Bone Miner Res, 20: 447–454. doi: 10.1359/JBMR.041120
- Issue online: 4 DEC 2009
- Version of Record online: 29 NOV 2004
- Manuscript Accepted: 15 OCT 2004
- Manuscript Revised: 15 JUL 2004
- Manuscript Received: 24 MAR 2004
- animal models;
- vitamin D receptor;
- vitamin D
The functional status and mechanism of increased VDR in GHS rats were investigated. Basal VDR and calbindins were increased in GHS rats. 1,25(OH)2D3 increased VDR and calbindins in controls but not GHS rats. VDR half-life was prolonged in GHS rats. This study supports the mechanism and functional status of elevated VDR in GHS rats.
Introduction: Genetic hypercalciuric stone-forming (GHS) rats form calcium kidney stones from hypercalciuria arising from increased intestinal calcium absorption and bone resorption and decreased renal calcium reabsorption. Normal serum 1,25-dihydroxyvitamin D3 ‘1,25(OH)2D3’ levels and increased vitamin D receptor (VDR) protein suggest that high rates of expression of vitamin D-responsive genes may mediate the hypercalciuria. The mechanism of elevated VDR and state of receptor function are not known.
Materials and Methods: GHS and non-stone-forming control (NC) male rats (mean, 249 g), fed a normal calcium diet, were injected intraperitoneally with 1,25(OH)2D3 (30 ng/100 g BW) or vehicle 24 h before cycloheximide (6 mg/100 g, IP) and were killed 0–8 h afterward. Duodenal VDR was measured by ELISA and Western blot, and duodenal and kidney calbindins (9 and 28 kDa) were measured by Western blots.
Results and Conclusions: Duodenal VDR protein by Western blot was increased 2-fold in GHS versus NC rats (633 ± 62 versus 388 ± 48 fmol/mg protein, n = 4, p < 0.02), and 1,25(OH)2D3 increased VDR and calbindins (9 and 28 kDa) further in NC but not GHS rats. Duodenal VDR half-life was prolonged in GHS rats (2.59 ± 0.2 versus 1.81 ± 0.2 h, p < 0.001). 1,25(OH)2D3 prolonged duodenal VDR half-life in NC rats to that of untreated GHS rats (2.59 ± 0.2 versus 2.83 ± 0.3 h, not significant). This study supports the hypothesis that prolongation of VDR half-life increases VDR tissue levels and mediates increased VDR-regulated genes that result in hypercalciuria through actions on vitamin D-regulated calcium transport in intestine, bone, and kidney.