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Functional Relationship between the Molecules Involved in the Renal Phosphate Reabsorption

参与肾磷酸盐重吸收的分子之间的功能关系

基本信息

批准号：
18590921
负责人：
MICHIGAMI Toshimi
金额：
$ 2.45万
依托单位：
Research Institute, Osaka Medical Center for Maternal and Child Health
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590921/
关键词：
phosphate FGF23 megain klotho Na^+Pi co-transporter klotho 無機リン酸 ERK1 2 ナトリウム・リン酸共輸送担体リン酸再吸収 FGF-23 megalin

项目摘要

Although it has been revealed that several molecules are involved in the regulation of renal phosphate reabsorption, the functional relationship between these molecules remains to be elucidated. In the current study, we aimed to clarify the mechanisms by which these molecules coordinate to regulate renal phosphate reabsorption. We have previously found that megalin-dependent endocytosis is involved in renal phosphate reabsorption via the regulation of subcellular distribution of type IIa Na^+/Pi co-transporter. Therefore, we first examined whether megalin-dependent endocytosis affect the action of FGF23 as a phosphatunc hormone. The disturbance of megalin-dependent endocytosis using soluble form of receptor associated protein(RAP) resulted in the reduced serum level of FGF23 in mice. This observation recapitulates the reduced serum FGF23 in human patients with Fanconi syndrome, suggesting that FGF23 is filtered in glomerulus and excreted in urine. We also examined the effect of extracellular phosphate(Pi) itself on the FGF23 signaling using HEK293 human embryonic kidney cells. We found that increased extracellular Pi resulted in the signal transduction in the cells, and it shared the downstream signaling network with FGF23. These results suggest that extracellular Pi itself affect the responsiveness of renal tubular cells to FGF23.

尽管已经揭示了几种分子参与肾磷酸盐重吸收的调节，但这些分子之间的功能关系仍有待阐明。在当前的研究中，我们的目的是阐明这些分子协调调节肾磷酸盐重吸收的机制。我们之前发现巨蛋白依赖性内吞作用通过调节 IIa 型 Na^+/Pi 协同转运蛋白的亚细胞分布参与肾磷酸盐重吸收。因此，我们首先检查巨蛋白依赖性内吞作用是否影响 FGF23 作为磷酸化激素的作用。使用可溶形式的受体相关蛋白 (RAP) 干扰巨蛋白依赖性内吞作用导致小鼠血清 FGF23 水平降低。这一观察结果概括了 Fanconi 综合征患者血清 FGF23 的降低，表明 FGF23 在肾小球中过滤并通过尿液排出。我们还使用 HEK293 人胚胎肾细胞检查了细胞外磷酸盐 (Pi) 本身对 FGF23 信号传导的影响。我们发现细胞外Pi的增加导致细胞内的信号转导，并且它与FGF23共享下游信号网络。这些结果表明细胞外Pi本身影响肾小管细胞对FGF23的反应性。