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Mechanism and Function of High Vitamin D Receptor Levels in Genetic Hypercalciuric Stone‐Forming Rats
Author(s) -
Karnauskas Alexander J,
van Leeuwen Johannes PTM,
van den Bemd GertJan CM,
Kathpalia Paru P,
DeLuca Hector F,
Bushinsky David A,
Favus Murray J
Publication year - 2005
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1359/jbmr.041120
Subject(s) - calcitriol receptor , medicine , endocrinology , hypercalciuria , vitamin d and neurology , calcium sensing receptor , calcium , western blot , reabsorption , receptor , chemistry , kidney , parathyroid hormone , biochemistry , gene
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 D 3 ‘1,25(OH) 2 D 3 ’ 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) 2 D 3 (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) 2 D 3 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) 2 D 3 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.