Endocrinology, Vol 137, 2938-2946, Copyright © 1996 by Endocrine Society

ARTICLES

Transcriptional regulation and renal localization of 1,25- dihydroxyvitamin D3-24-hydroxylase gene expression: effects of the Hyp mutation and 1,25-dihydroxyvitamin D3

S Roy and HS Tenenhouse
Medical Research Council Genetics Group, McGill University-Montreal Children's Hospital Research Institute, Montreal, Quebec, Canada.

X-Linked hypophosphatemic (HYP) mice respond to low phosphate (Pi) intake with a fall in the serum concentration of 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] and an increase in the renal activity of 1,25-(OH)2D3- 24-hydroxylase (24-hydroxylase), the first enzyme in the C-24 oxidation pathway that degrades 1,25-(OH)2D3 to its final inactivation product. In contrast, normal mice respond to a low Pi diet with an adaptive increase in serum 1,25-(OH)2D3 levels and no change in renal 24- hydroxylase. The low Pi response in Hyp mice involves a 3-fold increase in renal 24-hydroxylase maximum velocity and a corresponding increase in 24-hydroxylase immunoreactive protein and messenger RNA (mRNA). To determine the mechanism for the increase in 24-hydroxylase mRNA in the mutant strain, we examined the effect of actinomycin D on renal 24- hydroxylase mRNA abundance and measured renal 24-hydroxylase gene transcription by nuclear run-off assay in Hyp mice fed control and low Pi diets for 4 h. Vehicle and 1,25-(OH)2D3-treated normal mice were also studied 2-4 h post-treatment. Actinomycin D abrogated the increase in renal 24-hydroxylase mRNA elicited by a low Pi diet in Hyp mice and by 1,25-(OH)2D3 in both normal and Hyp mice. 24-Hydroxylase gene transcription, relative to that of glyceraldehyde-3-phosphate dehydrogenase, was increased 2-fold by feeding the low Pi diet to Hyp mice (n = 4; P < 0.05) and 5.4-fold by 1,25-(OH)2D3 administration to normal mice (n = 3; P < 0.01). In situ hybridization localized 24- hydroxylase transcripts to the proximal tubule of normal and mutant mice fed control and low Pi diets and showed that the 1,25(OH)2D3- induced increase in 24-hydroxylase mRNA occurred in the same nephron segment. The present study demonstrates that 1) transcriptional activation can account for the increase in renal 24-hydroxylase mRNA in Pi-deprived Hyp mice and for 24-hydroxylase mRNA induction by 1,25- (OH)2D3; and 2) the renal proximal tubule is the primary site of increased expression of 24-hydroxylase mRNA.

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