Proximal Tubule Transport Defect in Hyp Mice

描述（由申请人提供）：x连锁低磷血症的特征是肾磷酸盐消耗导致低磷血症，以及相对缺乏125 (OH)2维生素d。这些缺陷被认为是由于循环磷酸蛋白FGF-23水平升高所致。目前的治疗包括口服磷酸盐和1,25(OH)2维生素D，可改善佝偻病，但可导致甲状旁腺功能亢进、高钙血症、高钙尿症和肾钙质沉着症。我们发现Hyp小鼠具有与人类x连锁低磷血症相同的遗传缺陷，其尿前列腺素排泄率和近端小管PGE2含量高于C57/B6小鼠。体内和体外给药吲哚美辛完全使高磷尿、离体灌注小管运输缺陷和刷状膜小泡NaPi共转运蛋白丰度恢复正常。此外，我们发现Hyp小鼠的磷酸盐转运缺陷和NaPi转运体的缺乏在体外孵育一小时内是可逆的，这表明磷酸盐快速冲洗。我们证明，在小鼠和家兔近端小管中添加FGF-23可抑制磷酸盐运输。本提案的第一个目的是表征假定的磷酸蛋白FGF-23如何抑制离体灌注小鼠近端小管中的磷酸盐运输。第二个目的是确定PGE2在x连锁低磷血症中近端小管磷酸盐运输调节中的作用。第三个目的是确定异常前列腺素的产生在Hyp小鼠骨和肾异常的发病机制中的作用。我们将研究慢性吲哚美辛治疗是否能改善Hyp小鼠的骨病、生长和维生素D代谢异常。我们发现慢性吲哚美辛治疗能增加Hyp小鼠的血清磷酸盐。这些研究不仅将研究这种疾病的发病机制，而且将直接研究吲哚美辛是否可能代表一种治疗这种疾病的新方法。

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.