Regulation of phosphorus homeostasis by the type iia na/phosphate cotransporter

The type IIa Na/phosphate (Pi) cotransporter (Npt2a) is expressed in the brush border membrane (BBM) of renal proximal tubular cells where the bulk of filtered Pi is reabsorbed. Disruption of the Npt2a gene in mice elicits hypophosphatemia, renal Pi wasting, and an 80% decrease in renal BBM Na/Pi cotransport, and led to the demonstration that Npt2a is the target for hormonal and dietary regulation of renal Pi reabsorption. Regulation is achieved by changes in BBM abundance of Npt2a protein and requires the interaction of Npt2a with various scaffolding and regulatory proteins. Molecular studies in patients with renal Pi wasting resulted in the identification of novel regulators of Pi homeostasis: fibroblast growth factor-23 (FGF-23) and a phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX). In mouse models, increased FGF-23 production or loss of Phex function causes hypophosphatemia and decreased renal Pi reabsorption, secondary to decreased BBM Npt2a protein abundance. Thus, Npt2a plays a major role in the maintenance of Pi homeostasis in both health and disease.