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Phosphatonin washout in Hyp mice proximal tubules: evidence for posttranscriptional regulation

Departments of ¹Pediatrics and ²Internal Medicine Charles and ³Jane Pak Center of Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas

Submitted 14 June 2004 ; accepted in final form 27 September 2004

X-linked hypophosphatemia is the most common inherited form of rickets. It is characterized by renal phosphate wasting, leading to hypophosphatemia and an inappropriately normal or low serum level of 1,25(OH)₂ vitamin D. Previous studies have pointed to a circulating factor or phosphatonin-inhibiting phosphate transport by decreasing mRNA of the proximal tubule NaP_i cotransporter NaPi-2A. The present study examined the hypothesis that there was also posttranscriptional regulation of the NaPi-2A cotransporter in Hyp mice proximal tubules and whether the phosphate transport defect in Hyp mice persisted when they were studied in vitro. We found that the rate of phosphate transport in Hyp mice was <50% that in C57/B6 control mice. While phosphate transport remained stable during incubation with time in C57/B6 mice proximal tubules, it increased from 0.46 ± 0.47 to 1.83 ± 0.40 pmol·mm^–1·min^–1 in Hyp proximal tubules (P < 0.01) consistent with phosphatonin washout in Hyp proximal tubules perfused in vitro. This time-dependent increase in phosphate transport was still observed in the presence of cycloheximide. There was also a reduction of proximal tubule apical NaPi-2A expression from Hyp mice compared with C57/B6 mice using single-tubule immunohistochemistry. Using immunohistochemistry, we demonstrate an increase in apical expression of the NaPi-2A transporter in proximal tubules perfused in vitro in Hyp mice even in the presence of bath cycloheximide. The increase in apical expression of the NaPi-2A transporter in proximal tubules perfused in vitro in Hyp mice was blocked by colchicine. These data are consistent with a rapidly reversible posttranscriptional defect in Hyp mice causing a reduction in phosphate transport.

phosphate transport; proximal tubule transport; in vitro microperfusion; X-linked hypophosphatemia

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