Renal phosphate transport and vitamin D metabolism in X-linked hypophosphatemic Gy mice: responses to phosphate deprivation.
Two closely linked, nonallelic genes, Gy and Hyp, result in X-linked hypophosphatemia in mice. The present studies in Gy mice were undertaken to determine whether renal brush-border membrane Na(+)-phosphate cotransport kinetics and adaptive responses of renal phosphate transport and vitamin D metabolism to phosphate deprivation are comparable in the two mutant strains. Transport studies in purified brush-border membrane vesicles over a phosphate concentration range of 10-500 microM demonstrated that the apparent maximum velocity of the high affinity transport system is significantly decreased in Gy mice (420 +/- 110 vs. 710 +/- 100 pmol/mg protein.6 sec, Gy vs. normal; mean +/- SE; P less than 0.05), whereas the affinity of the cotransporter for phosphate is unchanged (apparent Km, 25 +/- 3 vs. 27 +/- 2 microM; NS). Feeding a low phosphate diet results in a significant fall in plasma phosphate and an increase in brush-border membrane Na(+)-phosphate cotransport in both normal (568 +/- 40 to 1416 +/- 139 pmol/mg protein.6 sec; P less than 0.01) and Gy mice (407 +/- 27 to 1236 +/- 132 pmol/mg protein.6 sec; P less than 0.01). While the low phosphate diet elicited a rise in plasma 1,25-dihydroxyvitamin D in normal mice (51 +/- 12 to 158 +/- 12 pM; P less than 0.01), a fall in plasma hormone levels was evident in phosphate-deprived Gy mice (90 +/- 22 to 23 +/- 11 pM; P less than 0.01). Phosphate deprivation decreased 25-hydroxyvitamin D-24-hydroxylase (24-hydroxylase), the first enzyme in the renal vitamin D catabolic pathway, in normal mice (117 +/- 21 to 69 +/- 8 fmol/mg protein.min), but increased enzyme activity in Gy mice (172 +/- 14 to 240 +/- 18 fmol/mg protein.min; P less than 0.05). Moreover, under both dietary conditions, 24-hydroxylase activity was significantly elevated in Gy mice. The present results demonstrate that hypophosphatemia in Gy mice can be attributed to a decrease in the maximum velocity of the high affinity Na(+)-phosphate cotransport process in renal brush-border membranes. Our results also show that while renal brush-border membrane phosphate transport is appropriately modulated by phosphate in Gy mice, phosphate regulation of vitamin D metabolism is apparently impaired in the mutant strain. The present findings provide evidence for phenotypic similarities between murine Gy and Hyp mutations.
Tenenhouse
H S
HS
Department of Pediatrics, McGill University, Montreal, Quebec, Canada.
Meyer
R A
RA
Mandla
S
S
Meyer
M H
MH
Gray
R W
RW
D000818:Animals; D001692:Biological Transport; D002117:Calcitriol / Q000097:blood; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004032:Diet; D007015:Hypophosphatemia, Familial / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism* / Q000648:ultrastructure; D007700:Kinetics; D051379:Mice; D008817:Mice, Mutant Strains; D008871:Microvilli / Q000378:metabolism; D010710:Phosphates / Q000008:administration & dosage / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism; D013250:Steroid Hydroxylases / Q000378:metabolism; D014807:Vitamin D / Q000378:metabolism*; D065668:Vitamin D3 24-Hydroxylase; D014960:X Chromosome
D010710:Phosphates; D014807:Vitamin D; D003577:Cytochrome P-450 Enzyme System; D012964:Sodium; D013250:Steroid Hydroxylases; D065668:Vitamin D3 24-Hydroxylase; D002117:Calcitriol