Functional Relationship between the Molecules Involved in the Renal Phosphate Reabsorption

虽然已经发现有几个分子参与了肾脏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。在目前的研究中，我们旨在阐明这些分子协调调节肾脏磷酸盐重吸收的机制。我们之前已经发现，meggalin依赖性内吞作用通过调节IIa型Na^+/Pi共转运蛋白的亚细胞分布参与肾磷酸重吸收。因此，我们首先研究了meggalin依赖性内吞作用是否会影响FGF23作为一种磷酸激素的作用。利用受体相关蛋白（RAP）的可溶性形式干扰巨噬蛋白依赖的内吞作用导致小鼠血清FGF23水平降低。这一观察结果概括了人类范可尼综合征患者血清中FGF23的减少，表明FGF23在肾小球中被过滤并随尿液排出。我们还利用HEK293人胚胎肾细胞检测了细胞外磷酸盐（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。

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.