AJP - Endocrinology and Metabolism, Vol 259, Issue 6 E814-E821, Copyright © 1990 by American Physiological Society
Renal 25-hydroxyvitamin D-1 alpha-hydroxylase activity and mitochondrial phosphate transport in Hyp mice
T. O. Carpenter and T. Shiratori
Department of Pediatrics (Endocrinology), Yale University School of Medicine, New Haven, Connecticut 06510.
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.
