Proximal Tubule Transport Defect in Hyp Mice

Hyp 小鼠的近端小管运输缺陷

• 批准号: 6863584
• 负责人: MICHEL GERARD BAUM
• 金额: $ 23.4万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-01 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6863584
• 关键词: brush border membrane; enzyme activity; fibroblast growth factor; genetically modified animals; hypophosphatemia; indomethacin; kidney disorder chemotherapy; kidney pharmacology; laboratory mouse; laboratory rabbit; mitogen activated protein kinase; osteomalacia; polymerase chain reaction; prostaglandin E; protein kinase C; renal tubular transport; renal tubule; rickets; vitamin D deficiency; vitamin D resistant rickets

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.

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 1,25(OH)2 维生素 D 相对缺乏。这些缺陷被认为是由于循环磷酸钙水平增加所致，FGF-23。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，具有与人类相同的X连锁低磷血症遗传缺陷的Hyp小鼠，其尿前列腺素排泄率和近曲小管PGE2含量均高于C57/B6小鼠。体内和体外给予吲哚美辛可使高磷酸盐尿症、离体灌注小管中的转运缺陷和刷状缘膜囊泡中 NaPi 协同转运蛋白丰度完全正常化。此外，我们发现 Hyp 小鼠中的磷酸盐转运缺陷和 NaPi 转运蛋白的缺乏在体外孵育一小时内是可逆的，这表明磷酸盐快速被清除。我们证明，管腔添加 FGF-23 可抑制小鼠和兔子近曲小管中的磷酸盐转运。该提案的第一个目的是描述假定的磷酸钙蛋白 FGF-23 如何抑制离体灌注小鼠近端小管中的磷酸盐转运。第二个目的是确定 PGE2 在 X 连锁低磷血症中近曲小管磷酸盐转运调节中的作用。第三个目的是确定前列腺素生成异常在 Hyp 小鼠骨和肾脏异常发病机制中的作用。我们发现长期吲哚美辛治疗会增加 Hyp 小鼠的血清磷酸盐，我们将检查是否可以改善其骨病、生长和维生素 D 代谢异常。这些研究不仅将检查这种疾病的发病机制，还将直接检查吲哚美辛是否可能代表这种疾病的新疗法。