Intestinal responses to 1,25 dihydroxyvitamin D are not improved by higher intestinal VDR levels resulting from intestine-specific transgenic expression of VDR in mice

Abstract

Intestinal calcium (Ca) absorption depends upon vitamin D signaling through the vitamin D receptor (VDR) in the proximal and distal intestine while lower VDR content causes intestinal resistance to 1,25 dihydroxyvitamin D (1,25(OH)2 D) action. We tested whether intestinal responsiveness to 1,25(OH)2 D is increased in mice with higher than normal VDR levels resulting from transgenic VDR expression in the whole intestine (villin promoter-human VDR transgene, HV2). Wild type (WT) and HV2 mice were treated with 0, 0.15, or 0.3 ng 1,25(OH)2 D/g body weight (BW) (n = 6/dose) for 6 h. 1,25(OH)2 D significantly induced Cyp24a1, Trpv6, and S100 g mRNA in duodenum (Dd) of WT mice but induction was not higher in HV2 mice. We next tested whether higher intestinal VDR could protect mice from the consequences of low dietary Ca intake. WT and HV2 mice were fed diets with 0.125, 0.25, 0.5 (reference), or 1% Ca from weaning to 3 months of age (n = 9/diet/genotype). Dietary Ca restriction caused a dose dependent increase in serum 1,25(OH)2 D, Dd TRPV6, and Dd S100 g mRNA in WT mice and the effect was greater in HV2 mice. While Ca absorption was increased by low Ca intake, there was no difference in Ca absorption between HV2 and WT mice. Similarly, while bone density and microstructure were reduced by low Ca intake in WT mice, high intestinal VDR in HV2 mice did not protect bone in mice fed low Ca diets. Thus, while intestinal VDR and vitamin D signaling are essential for normal Ca metabolism during growth, our data demonstrate that higher than normal intestinal VDR levels do not improve the intestinal response to either 1,25(OH)2 D injection or to elevated 1,25(OH)2 D levels resulting from the physiologic adaptation to low Ca diets.