Proximal Tubule Transport Defect in Hyp Mice

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DESCRIPTION (provided by applicant): X-linked hypophosphatemia is characterized by renal phosphate wasting resulting in hypophosphatemia, and a relative deficiency of 1,25(OH)2 vitamin D. These defects are thought to be due to increased levels of a circulating phosphatonin, FGF-23. Current therapy includes administration of oral phosphate and 1,25(OH)2 vitamin D which results in improvement of rickets but can result in hyperparathyroidism, hypercalcemia, hypercalciuria and nephrocalcinosis. We have found that the Hyp mouse, which has the same genetic defect as humans with X-linked hypophosphatemia, has a higher rate of urinary prostaglandin excretion and proximal tubule PGE2 content than C57/B6 mice. Indomethacin administration in vivo and in vitro totally normalizes the hyperphosphaturia, the transport defect in isolated perfused tubules and NaPi co-transporter abundance in brush border membrane vesicles. In addition we find that the phosphate transport defect and the paucity of NaPi transporters in Hyp mice are reversible within an hour of incubation in vitro suggesting rapid phosphatonin washout. We demonstrate that luminal addition of FGF-23 inhibits phosphate transport in the mouse and rabbit proximal tubule. The first Aim of this proposal is to characterize how the putative phosphatonin, FGF-23, inhibits phosphate transport in isolated perfused mouse proximal tubules. The second Aim is to determine the role of PGE2 in the regulation of proximal tubule phosphate transport in X-linked hypophosphatemia. The third Aim is to determine the role of abnormal prostaglandin production in the pathogenesis of the bone and renal abnormalities in Hyp mice. We will examine if chronic indomethacin therapy, which we find increases serum phosphate in Hyp mice, improves their bone disease, growth and abnormal vitamin D metabolism. These studies will not only examine the pathogenesis of this disorder, but will directly examine if indomethacin potentially represents a novel therapy for this disease.