Intestinal resistance to 1,25 dihydroxyvitamin D in mice heterozygous for the vitamin D receptor knockout allele

We tested the hypothesis that low vitamin D receptor ( VDR) level causes intestinal vitamin D resistance and intestinal calcium ( Ca) malabsorption. To do so, we examined vitamin D regulated duodenal Ca absorption and gene expression [ transient receptor potential channel, vallinoid subfamily member 6 ( TRPV6), 24- hydroxylase, calbindin D-9k ( CaBP) mRNA, and CaBP protein] in wild- type mice and mice with reduced tissue VDR levels [i.e. heterozygotes for the VDR gene knockout ( HT)]. Induction of 24- hydroxylase mRNA levels by 1,25 dihydroxyvitamin D-3 [ 1,25( OH)(2) D3] injection was significantly reduced in the duodenum and kidney of HT mice in both time-course and dose-response experiments. TRPV6 and CaBP mRNA levels in duodenum were significantly induced after 1,25( OH)(2)D-3 injection, but there was no difference in response between wild- type and HT mice. Feeding a low-calcium diet for 1 wk increased plasma PTH, renal 1 alpha- hydroxylase ( CYP27B1) mRNA level, and plasma 1,25( OH)(2) D3, and this response was greater in HT mice ( by 88, 55, and 37% higher, respectively). In contrast, duodenal TRPV6 and CaBP mRNA were not higher in HT mice fed the low-calcium diet. However, the response of duodenal Ca absorption and CaBP protein to increasing 1,25( OH)(2) D3 levels was blunted by 40% in HT mice. Our data show that low VDR levels lead to resistance of intestinal Ca absorption to 1,25( OH)(2) D3, and this resistance may be due to a role for the VDR ( and VDR level) in the translation of CaBP.