Increased renal 25-hydroxyvitamin D3-24-hydroxylase messenger ribonucleic acid and immunoreactive protein in phosphate-deprived Hyp mice: a mechanism for accelerated 1,25-dihydroxyvitamin D3 catabolism in X-linked hypophosphatemic rickets.
X-Linked Hyp mice exhibit rachitic bone disease, hypophosphatemia, impaired renal phosphate reabsorption, and abnormal regulation of renal 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] metabolism. We demonstrated that phosphate deprivation of Hyp mice, but not normal littermates, elicits a dramatic fall in serum 1,25-(OH)2D levels and an increase in renal 1,25-(OH)2D3 catabolism that can be ascribed to an increase in the activity of renal mitochondrial 25-hydroxyvitamin D3-24-hydroxylase (24-hydroxylase), the first enzyme in the C-24 oxidation pathway. The present study was undertaken to elucidate the mechanism for the increase in renal 24-hydroxylase activity in phosphate-deprived Hyp mice. Phosphate deprivation of Hyp mice resulted in a 3-fold increase in the maximum velocity for 24-hydroxylase (n = 5; P < 0.001) accompanied by an increase in 24-hydroxylase immunoreactive protein relative to the level of ornithine aminotransferase. Phosphate deprivation of Hyp mice also elicited a 3-fold increase in renal 24-hydroxylase mRNA abundance relative to that of beta-actin mRNA (n = 7; P < 0.001). The increase in 24-hydroxylase mRNA was specific to the kidney and was evident as early as 1 day of the low phosphate diet. Phosphate deprivation had no effect on renal 24-hydroxylase immunoreactive protein or mRNA in normal littermates. In contrast to the abnormal 24-hydroxylase response to dietary phosphate, Hyp mice exhibited an appropriate increase in renal 24-hydroxylase mRNA and catalytic activity in response to increasing doses of 1,25-(OH)2D3. The present results demonstrate that elevated renal 24-hydroxylase activity in phosphate-deprived Hyp mice can be ascribed to an increase in the abundance of 24-hydroxylase mRNA and protein and suggest that inappropriate regulation of 1,25-(OH)2D3 catabolism in Hyp mice occurs at the pretranslational level.
Roy
S
S
Department of Biology, McGill University-Montreal Children's Hospital Research Institute, Quebec, Canada.
Martel
J
J
Ma
S
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Tenenhouse
H S
HS
D000818:Animals; D002117:Calcitriol / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D008040:Genetic Linkage; D017674:Hypophosphatemia / Q000235:genetics; D007668:Kidney / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL / Q000235:genetics; D009154:Mutation; D010710:Phosphates / Q000172:deficiency*; D012333:RNA, Messenger / Q000378:metabolism*; D012279:Rickets / Q000235:genetics; D013250:Steroid Hydroxylases / Q000235:genetics* / Q000378:metabolism*; D065668:Vitamin D3 24-Hydroxylase; D014960:X Chromosome
D010710:Phosphates; D012333:RNA, Messenger; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D065668:Vitamin D3 24-Hydroxylase; D002117:Calcitriol