title: Renal 25-hydroxyvitamin D-1 alpha-hydroxylase activity and mitochondrial phosphate transport in Hyp mice.
abstract: The Hyp mouse is a homologue of the X chromosome-linked human disease, familial hypophosphatemic rickets (FHR). In FHR, reduced renal tubular brush-border membrane transport of phosphate results in hypophosphatemia and rickets. Both humans with FHR and Hyp mice have abnormal regulation of 25-hydroxyvitamin D-1 alpha-hydroxylase (1 alpha-hydroxylase), a mitochondrial enzyme found in proximal renal tubular cell epithelia, the apparent site of defective brush-border membrane phosphate transport. No common pathophysiology for these defects has been demonstrated. We hypothesized that phosphate transport may be present in renal mitochondria from Hyp mice and that its regulation may be deranged in parallel with the mitochondrial 1 alpha-hydroxylase. Using inhibitor-stop techniques described for measurement of phosphate transport in liver mitochondria, we examined mitochondria in normal and Hyp mouse kidney and found them to be comparable. We performed manipulations known to alter 1 alpha-hydroxylase differentially in normal and Hyp mice, i.e., phosphorus deprivation and phosphorus loading, and found no effect on mitochondrial phosphate transport. We also subjected Hyp and normal mice to calcium and vitamin D deprivation; this maneuver resulted in no significant changes in mitochondrial phosphate transport in Hyp or normal mice but confirmed the earlier observation that 1 alpha-hydroxylase activity is stimulated to a greater degree in normal mice than Hyp mice after this diet. Furthermore, administration of 1,25-hydroxyvitamin D3 depresses 1 alpha-hydroxylase activity in mitochondria from both normal and Hyp mice but has no effect on mitochondrial phosphate transport. We conclude that the mechanism of abnormal vitamin D metabolism in Hyp mice is not related to a primary defect in renal mitochondrial phosphate transport.
authors: Department of Pediatrics (Endocrinology), Yale University School of Medicine, New Haven, Connecticut 06510.
authors: T O
authors: TO
authors: Carpenter
authors: T
authors: T
authors: Shiratori
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000378:metabolism*; D000818:Animals; D007015:Hypophosphatemia, Familial / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism*; D007700:Kinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008928:Mitochondria / Q000378:metabolism*; D010710:Phosphates / Q000378:metabolism*; D012016:Reference Values
chemical_list: D010710:Phosphates; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase