SODIUM-PHOSPHATE TRANSPORTER ADAPTATION TO DIETARY PHOSPHATE DEPRIVATION IN NORMAL AND HYPOPHOSPHATEMIC MICE

The X-linked hypophosphatemic (Hyp) mouse is a model for hypophosphatemic vitamin D-resistant rickets and is a homologue of human X-linked hypophosphatemia. The defect in the Hyp mouse appears to be related to decreased renal tubular reabsorption of P-i via the renal brush-border membrane (Na+-P-i) transporter. Dietary P-i deprivation upregulates Na+-P-i transport activity in brush-border membrane vesicles (BBMV) 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 P-i deprivation on the renal Na+-P-i transporter. Low P-i diet upregulated Na+-P-i transporter activity in isolated BBMV by 2.1-fold in normal and Hyp mice (n = 3, P = 0.01). Low P-i 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+-P-i transporter message levels (n = 3, P = 0.028). The increase in message level encoding the Na+-P-i transporter stimulated increased Na+-dependent P-i uptake by Xenopus laevis oocytes when poly(A)(+) RNA was injected into them from mice on low P-i diet (similar to 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 P-i deprivation. We conclude that the upregulation in renal Na+-P-i transporter activity induced by P-i deprivation in both normal and Hyp mice is the result of an increased mRNA level encoding the Na+-P-i transporter, which leads to increased amounts of immunoreactive and functional protein.