The molecular defect in the renal sodium-phosphate transporter expression pathway of Gyro (Gy) mice is distinct from that of hypophosphatemic (Hyp) mice.

Two animal models of the human disorder hypophosphatemic vitamin D-resistant rickets exist, the Hyp and Gy mice. Affected mice and humans both manifest an X-linked phenotype, and show decreased Na+/Pi transport activity in the renal proximal tubules, which is characterized by a decreased maximal velocity (Vmax). The defect in Hyp mice is most likely due to a decreased transcription rate of the renal Na+/Pi transporter gene. The current studies were designed to define the molecular defect in the Gy mice. Sodium-dependent uptake of phosphate (Pi) in renal BBMV showed uptake levels of 170.58 +/- 25 and 66.00 +/- 11 pmol x mg protein-1 x 6 s-1 in normal and Gy mice, respectively (n=3, P=0.0102). Glucose uptake levels in the BBMV were 1.94 +/- 0.87 and 1.91 +/- 0.35 pmol x mg protein-1 x 6 s-1 in normal and Gy mice, respectively (n=3). Northern blot analysis of kidney cortex in both mice revealed nearly equivalent message levels (normal/Gy=1.01 +/- 0.12, n=3). In situ hybridization localized the mRNA to the renal cortex in both mice and confirmed equal message levels. Western blot analysis of renal BBM proteins, using a polyclonal antiserum, showed one predominant band at 87 kDa in both mouse samples, with intensities being decreased in the Gy mice (normal/Gy=4.129 +/- 0.70, n=4, P< 0.04). Immunohistochemical analysis localized the protein to the apical membrane of proximal tubules in both mice. These results suggest that the molecular defect in the Gy mice is distinct from that in the Hyp mice, and furthermore, that the manifestation of the diseased phenotype in Gy mice is related to a different defect in the renal Na+/Pi transporter expression pathway. The molecular mechanism of the defect likely relates to protein processing, metabolic turnover rate, or translocation to the brush-border membrane. These results further suggest that two distinct X-linked factors modulate different steps in the expression pathway of the Na+/Pi transporter gene.