Transgenic expression of the human Vitamin D receptor (hVDR) in the duodenum of VDR-null mice attenuates the age-dependent decline in calcium absorption.
1,25(OH)(2)D(3) regulates calcium homeostasis through its actions in the intestine, bone, and kidney. These actions are mediated through the VDR. To determine if VDR's actions in the proximal small intestine can sufficiently restore calcium homeostasis, we generated transgenic mice expressing hVDR exclusively in the duodenum of mVDR-null mice by using the adenosine deaminase enhancer (hVDR+/mVDR-null). Unlike wild-type mice, hVDR+/mVDR-null mice express hVDR and VDR target genes only in the proximal small intestine. Despite having functional hVDR in the proximal small intestine, hVDR+/mVDR-null mice were hypocalcaemic when fed a normal rodent diet at weaning, like mVDR-null mice fed the same diet. The hypocalcemia in these mice is prevented if they are given the rescue diet before weaning. However, when 90-day-old rachitic mice were fed a rescue diet, serum calcium improved in hVDR+/mVDR-null mice, but not in mVDR-null mice. In conclusion, transgenic hVDR in the proximal small intestine of hVDR+/mVDR-null mice was transcriptionally active and regulated calcium absorption, but VDR actions elsewhere in the intestine are probably necessary to support adequate calcium homeostasis. In addition, hVDR+/mVDR-null mice responded better to the late rescue diet suggesting that expression of VDR in the proximal small intestine protected the calcium absorbing machinery from age-dependent decline.
Marks
Hilary D
HD
Department of Endocrine Neoplasia and Hormonal Disorders, Unit 435, The University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Fleet
James C
JC
Peleg
Sara
S
D000375:Aging / Q000502:physiology*; D000818:Animals; D002118:Calcium / Q000097:blood*; D004386:Duodenum / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D018167:Receptors, Calcitriol / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013250:Steroid Hydroxylases / Q000235:genetics; D065668:Vitamin D3 24-Hydroxylase
D018167:Receptors, Calcitriol; D011994:Recombinant Proteins; D013250:Steroid Hydroxylases; D065668:Vitamin D3 24-Hydroxylase; D002118:Calcium