Inorganic phosphate transportsome and human disease

维持恒定的PI循环水平依赖于肾脏的活动。在肾脏中已发现两种类型的Na/PI共转运体(Npt2a和Npt2c)。肾上皮细胞顶膜中Npt2a和Npt2c的丰富是PI动态平衡的主要决定因素。Npt2a基因敲除(KO)小鼠表现为尿磷排泄增加，肾BBM囊泡Na/PI共转运减少50%-70%，并出现低磷血症。Npt2a KO小鼠也高表达Npt2c，可能支持残留肾脏PI重吸收功能。Npt2a^&lt；-/-&gt；Npt2c；-/-&gt；-/-&gt；双基因敲除(DKO)小鼠的实验室和骨骼异常比只切除一个转运体(Npt2a或Npt2c)的动物更严重，这表明这两个分子在啮齿类动物和人类的PI稳态中具有相似的非多余作用。此外，我们还发现，人类Npt2c基因突变导致遗传性低磷软骨病伴高钙尿症(ITHRH)。在正确定位并插入上皮细胞质膜后，可能需要特定的蛋白质-蛋白质相互作用来稳定膜蛋白的最终定位。针对Napi-11的C末端(Npt2a和Npt2c)进行的经典酵母双杂交筛选显示，该共转运蛋白与几个含有PDZ结构域的蛋白质相互作用，这些蛋白质可能有助于Napi-11在顶膜上的稳定。Napi-he(Npt2c)与NHERF1和NHERF4相互作用。这些相互作用对NAPI-LLC顶端定位和调控的影响仍有待澄清。在这项研究中，我们发现了肾脏内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.