1,25-Dihydroxyvitamin D3 up-regulates the renal vitamin D receptor through indirect gene activation and receptor stabilization.
Expression of the vitamin D receptor (VDR) in the kidney and intestine plays a major role in calcium homeostasis and the metabolism of 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)). Calcium and 1,25(OH)(2)D(3)-mediated regulation of renal and duodenal VDR expression has been analyzed in vivo and the mechanisms responsible for the renal regulation have been studied in mouse kidney TCMK-1 cells. Vitamin D-deficient mice were maintained on diets containing either 0.02 or 0.47% calcium, with or without 50ng of 1,25(OH)(2)D(3) per day. Renal VDR levels were significantly higher in the vitamin D-deficient mice fed the 0.47% calcium diet vs. the calcium-restricted diet, and were increased 5-fold by 1,25(OH)(2)D(3) when dietary calcium was present. The renal VDR transcript was expressed at a basal level in the absence of calcium or 1,25(OH)(2)D(3); 50ng of 1,25(OH)(2)D(3) elevated renal VDR mRNA levels approximately 10-fold in the presence of calcium. Neither calcium nor 1,25(OH)(2)D(3) had any significant effect on duodenal VDR or VDR mRNA expression. In TCMK-1 cells, 1,25(OH)(2)D(3) increased receptor and VDR mRNA content in both low and adequate calcium medium. The 1,25(OH)(2)D(3)-mediated increase in VDR mRNA did not result from increased stability of the transcript. Further, the increase in mRNA was blocked by cycloheximide, indicating a requirement for protein synthesis and an indirect regulation of VDR transcription. Thus, both dietary serum calcium and 1,25-(OH)(2)D(3) are required for VDR expression in kidney but not in intestine where neither is required. The 1,25-(OH)(2)D(3) requirement can also be shown in TCMK-1 cells in vitro, while the calcium requirement was not found.
Healy
Kevin D
KD
Department of Biochemistry, College of Agricultural and Life sciences, University of Wisconsin-Madison, Madison, WI 53706, USA.
Frahm
Marc A
MA
DeLuca
Hector F
HF
D000818:Animals; D002117:Calcitriol / Q000008:administration & dosage / Q000494:pharmacology*; D002118:Calcium / Q000097:blood / Q000378:metabolism; D002136:Calcium, Dietary / Q000008:administration & dosage / Q000494:pharmacology*; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D007668:Kidney / Q000187:drug effects*; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000235:genetics* / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D015533:Transcriptional Activation; D015854:Up-Regulation / Q000187:drug effects*
D002136:Calcium, Dietary; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; D002117:Calcitriol; D002118:Calcium