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Mechanism and function of high vitamin D receptor levels in genetic hypercalciuric stone-forming rats.
J Bone Miner Res 2005; 20(3):447-54JB

Abstract

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)(2)D(3) 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.

Authors+Show Affiliations

Department of Medicine, University of Chicago Pritzker School of Medicine, Chicago, Illinois 60637, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15746989

Citation

Karnauskas, Alexander J., et al. "Mechanism and Function of High Vitamin D Receptor Levels in Genetic Hypercalciuric Stone-forming Rats." Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research, vol. 20, no. 3, 2005, pp. 447-54.
Karnauskas AJ, van Leeuwen JP, van den Bemd GJ, et al. Mechanism and function of high vitamin D receptor levels in genetic hypercalciuric stone-forming rats. J Bone Miner Res. 2005;20(3):447-54.
Karnauskas, A. J., van Leeuwen, J. P., van den Bemd, G. J., Kathpalia, P. P., DeLuca, H. F., Bushinsky, D. A., & Favus, M. J. (2005). Mechanism and function of high vitamin D receptor levels in genetic hypercalciuric stone-forming rats. Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research, 20(3), pp. 447-54.
Karnauskas AJ, et al. Mechanism and Function of High Vitamin D Receptor Levels in Genetic Hypercalciuric Stone-forming Rats. J Bone Miner Res. 2005;20(3):447-54. PubMed PMID: 15746989.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mechanism and function of high vitamin D receptor levels in genetic hypercalciuric stone-forming rats. AU - Karnauskas,Alexander J, AU - van Leeuwen,Johannes P T M, AU - van den Bemd,Gert-Jan C M, AU - Kathpalia,Paru P, AU - DeLuca,Hector F, AU - Bushinsky,David A, AU - Favus,Murray J, Y1 - 2004/11/29/ PY - 2004/03/24/received PY - 2004/07/15/revised PY - 2004/10/15/accepted PY - 2005/3/5/pubmed PY - 2005/6/24/medline PY - 2005/3/5/entrez SP - 447 EP - 54 JF - Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research JO - J. Bone Miner. Res. VL - 20 IS - 3 N2 - UNLABELLED: 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)(2)D(3) 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. SN - 0884-0431 UR - https://www.unboundmedicine.com/medline/citation/15746989/Mechanism_and_function_of_high_vitamin_D_receptor_levels_in_genetic_hypercalciuric_stone_forming_rats_ L2 - https://doi.org/10.1359/JBMR.041120 DB - PRIME DP - Unbound Medicine ER -