Molecular Nutrition Study for Inorganic Phosphate Metabolism

(JSNFS Award for Excellence in Research (2010))

Abstract

Phosphate is widely distributed in the body and is involved in cell signaling, energy metabolism, nucleic acid synthesis, and the maintenance of acid-base balance by urinary buffering. Homeostasis of inorganic phosphate (Pi) is an essential physiological function as manifested by syndromes that arise from hypo- or hyperphosphatemic states. Pi wasting is linked with rickets and osteomalacia, whereas hyperphosphatemia is associated with an increased risk cardiovascular disease. The maintenance of constant circulating levels of Pi depends on the coordinated activity of three major organs, the intestine the kidney, and the bone. Three types of Na/Pi co-transporters (SLC17, SLC20, SLC34) have been identified in the three major organs. Gene knockout mice have been created for the types I-III of Na/Pi co-transporters. Furthermore, the identification of genetic alterations in Mendelian disorders of hypophosphatemia and hyperphosphatemia has led to the isolation of novel genes (FGF-23/Klotho) and the identification of new roles for existing proteins in the control of Pi metabolism. The discovery of FGF23/klotho has clarified much of our understanding of abnormalities in phosphate and vitamin D metabolism in chronic kidney disease (CKD). Emerging data highlight the potential of FGF23 as a novel diagnostic to identify CKD patients at the highest risk for disease progression, cardiovascular disease, and death, and those who might benefit from early phosphate-related therapies before the onset of overt hyperphosphatemia. This review will summarized recent insights into the roles of Na/Pi-cotransporters in Pi homeostasis and will discuss how these discoveries have uncovered novel aspect of Pi homeostasis.