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Department of Biochemistry and Molecular Biology, University of Medicine and Dentistry of New Jersey-New Jersey Medical School and Graduate School of Biomedical Sciences, Newark, New Jersey 07103; Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, New Hampshire 03755; Department of Medicine, Mayo Clinic and Foundation, Mayo Medical School, Rochester, Minnesota 55905; Departments of Medicine and Biochemistry, University of New Mexico, Albuquerque, New Mexico 87131; Department of Biochemistry, University of Adelaide, Adelaide, South Australia 5025; and Department of Pediatrics, Women and Infants Hospital of Rhode Island, Providence, Rhode Island 02905
Previous studies
using microdissected nephron segments reported that the exclusive site
of renal 25-hydroxyvitamin
D3-24-hydroxylase (24OHase)
activity is the renal proximal convoluted tubule (PCT). We now report
the presence of 24OHase mRNA, protein, and activity in cells that are
devoid of markers of proximal tubules but express characteristics
highly specific for the distal tubule. 24OHase mRNA was undetectable in
vehicle-treated mouse distal convoluted tubule (DCT) cells but was
markedly induced when DCT cells were treated with 1,25 dihydroxyvitamin
D3
[1,25(OH)2D3].
24OHase protein and activity were also identified in DCT cells by
Western blot analysis and HPLC, respectively. 8-Bromo-cAMP (1 mM) or
parathyroid hormone [PTH-(1
34); 10 nM] was found to
potentiate the effect of
1,25(OH)2D3
on 24OHase mRNA. The stimulatory effect of cAMP or PTH on 24OHase
expression in DCT cells suggests differential regulation of 24OHase
expression in the PCT and DCT. In the presence of cAMP and
1,25(OH)2D3,
a four- to sixfold induction in vitamin D receptor (VDR) mRNA was
observed. VDR protein, as determined by Western blot analysis, was also
enhanced in the presence of cAMP. Transient transfection analysis in
DCT cells with rat 24OHase promoter deletion constructs demonstrated
that cAMP enhanced
1,25(OH)2D3-induced 24OHase transcription but this enhancement was not mediated by cAMP
response elements (CREs) in the 24OHase promoter. We conclude that
1) although the PCT is the major
site of localization of 24OHase, 24OHase mRNA and activity can also be
localized in the distal nephron; 2)
both PTH and cAMP modulate the induction of 24OHase expression by
1,25(OH)2D3
in DCT cells in a manner different from that reported in the PCT; and
3) in DCT cells, upregulation of VDR
levels by cAMP, and not an effect on CREs in the 24OHase promoter, is
one mechanism involved in the cAMP-mediated modulation of 24OHase transcription.
vitamin D regulation; parathyroid hormone
This article has been cited by other articles:
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