Inorganic phosphate transportsome and human disease

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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.