Regulation of Proximal Tubule Phosphate Transport: New Partners, New Pathways

Disorders of phosphate homeostasis are common but difficult to treat. The major organ systems responsible for phosphate homeostasis are the intestine, bone, kidney, and parathyroid gland. Overall, kidney handling of phosphate is the major regulator of both serum phosphate levels and overall phosphate homeostasis. However, our ability to manipulate kidney phosphate handling has been very limited. Npt2a has been more thoroughly investigated than Npt2c, but recent studies identifying the role of Npt2c in human disease have uncovered key differences in the role of Npt2c in mice and humans. Recent studies have identified new proteins, such as TMEM174 and RGS14, that are involved in the regulation of the major sodium-dependent phosphate transporters in the kidney. Additionally, newer chemical agents to alter the function of these transporters have been developed. The purpose of this review is to highlight these new advances, place them in the context of our current knowledge of phosphate homeostasis, and explore potential new approaches to abnormalities of phosphate homeostasis. The recent discoveries suggest potential therapeutic targets for hyperphosphatemic conditions, such as chronic kidney disease and tumoral calcinosis, as well as for hypophosphatemic states, such as Fanconi syndrome, hypophosphatemic rickets, or transporter mutations.