Inorganic phosphate transportsome and human disease

周转率维持在恒定的循环水平取决于肾脏的活动。两种类型的Na/Pi共转运蛋白（Npt2a, Npt2c）已经在肾脏中被发现。肾上皮细胞顶膜中Npt2a和Npt2c的丰度是Pi稳态的主要决定因素。Npt2a敲除（KO）小鼠表现出尿Pi排泄增加，肾BBM囊泡Na/Pi共转运减少50%至70%，以及低磷血症。Npt2a KO小鼠也过表达Npt2c，可能支持残余肾Pi重吸收功能。实验和骨异常在Npt2a^<-/->Npt2c^<-/->双敲除（DKO）小鼠中比在仅消融一种转运体（Npt2a或Npt2c）的动物中更为深刻，表明这两种分子在啮齿动物和人类的Pi稳态中具有相似的非冗余作用。此外，我们发现人类Npt2c突变导致遗传性低磷血症佝偻病伴高钙尿症（ITHRH）。在正确靶向并插入上皮细胞的质膜后，可能需要特异性的蛋白-蛋白相互作用来稳定膜蛋白的最终定位。针对NaPi-ll的c端（Npt2a和Npt2c）进行的经典酵母双杂交筛选显示，该共转运体与几种含有PDZ结构域的蛋白相互作用，可能有助于在顶膜上稳定NaPi-ll。NaPi-He （Npt2c）被证明与NHERF1和NHERF4相互作用。这些相互作用对NaPi-llc的顶端定位和调控的影响仍有待澄清。在这项研究中，我们发现了肾中Pi转运体调控的新方面。

The maintenance of constant circulating levels of Pi depends on the activity of the kidney. Two types of Na/Pi co-transporters (Npt2a, Npt2c) have been identified in the kidney. The abundance of Npt2a and Npt2c in the apical membrane of the renal epithelial cells is a major determinant for Pi homeostasis. Npt2a knockout (KO) mice exhibit increased urinary Pi excretion, a 50% to 70% decrease in renal BBM vesicle Na/Pi cotransport, and hypophosphatemia. Npt2a KO mice also overexpress Npt2c, which may support residual renal Pi reabsorption function. Laboratory and bone abnormalities are more profound in Npt2a^<-/->Npt2c^<-/->double knockout (DKO) mice than in animals with ablation of only one transporter (Npt2a or Npt2c), indicating that both molecules have similar non-redundant roles in Pi homeostasis in rodents and humans. In addition, we found that the mutations of human Npt2c cause hereditary hypophosphatemie rickets with hypercalciuria (ITHRH)After correct targeting and insertion into the plasma membrane of epithelial cells, specific protein-protein interactions may be required to stabilize the final localization of membrane proteins. Classical yeast two-hybrid screens performed against the C-terminus of NaPi-ll (Npt2a and Npt2c) revealed interactions of this cotransporter with several PDZ domain containing proteins that may contribute to the stabilization of NaPi-ll at the apical membrane. NaPi-He (Npt2c) was shown to interact with NHERF1 and NHERF4. The consequences of these interactions for apical positioning and regulation of NaPi-llc remain to be clarified. In this study, we discovered new aspect of the regulation of the Pi transportsome in the kidney.