Sodium-phosphate (na+/pi) transporter adaptation to dietary
phosphate deprivation in normal and hypophosphatemic mice.
Collins, James F., Nada Bulus, and Fayez K. Ghishan.
Department of Pediatrics, Division of Gastroenterology/Nutrition,
and Department of Molecular Physiology and Biophysics, Vanderbilt
University School of Medicine, Nashville, TN 37232-2576
APStracts 2:0023G, 1995.
The hypophosphatemic (Hyp) mouse is an excellent model for
hypophosphatemic vitamin D-resistant rickets in man. The (Hyp) trait
has an X-linked mode of inheritance, and the (Hyp) mouse is a
homologue of human X-linked hypophosphatemia. The defect in the (Hyp)
mouse appears to be related to decreased renal tubular reabsorption
of phosphate via the renal brush-border membrane sodium-phosphate
(Na+/Pi) transporter. Dietary phosphate deprivation upregulates
Na+/Pi transport activity in brush-border membrane (BBM) vesicles
isolated from both normal and (Hyp) mice, however the molecular
mechanisms underlying this phenomenon are not known. The current
studies were designed to investigate the effect of phosphate
deprivation on Na+/Pi transporter activity in renal BBM vesicles, to
define the mRNA level encoding the transporter and its concomitant
expression in Xenopus laevis oocytes, and to investigate immunoreactive
protein levels. Low phosphate diet upregulated Na+/Pi transporter
activity in isolated BBM vesicles by 2.1-fold in normal mice and
(Hyp) mice (n=3, p = 0.01). Low Pi diet also induced a 1.9 +/- 0.3 fold
increase in normal mice and 2.9 +/- 0.4 fold increase in (Hyp) mice in
Na+/Pi transporter message levels (n=3, p = 0.028). The increase in
message level encoding the Na+/Pi transporter stimulated increased
Na+-dependent phosphate uptake by Xenopus laevis oocytes when poly (A)+
RNA was injected into them from mice on low Pi diet (approximately
1.67 fold in normal mice and 1.33 fold in [Hyp] mice).
Immunoreactive protein levels increased 2.3 +/- 0.4 fold in normal mice
and 8.2 +/- 0.5 in the (Hyp) mouse kidney cortexes (n=3, p = 0.0001 )
in response to dietary phosphate deprivation. Genotype differences
after low Pi diet between normal and (Hyp) were maintained in BBMV
and oocyte studies, however, the differences were much less
pronounced in the Northern and Western blot analyses. We conclude
that the upregulation in renal Na+/Pi transporter activity induced by
phosphate deprivation in both normal and (Hyp) mice is the result of
an increased mRNA level encoding the Na+/Pi transporter which leads
to increased amounts of immunoreactive and functional protein. These
data further suggest that the adaptive response to low Pi diet of
(Hyp) mice is similar to the adaptive response of the normal mice
when functional protein is considered. However, message and
immunoreactive protein level investigation studies show an increased
response in the (Hyp) mouse as compared to normals. The mechanism
underlying this discrepancy in the diet regulated expression pathway
of the Na+/Pi transporter in the (Hyp) mouse is currently unknown.
Received 15 August 1994; accepted in final form 11 January 1995.
APS Manuscript Number G303-4.
Article publication pending Am. J. Physiol. (Gastrointest. Liver
Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 23 February 1995.