Identification of the molecules which regulate the phosphate signaling network in mammalian kidney

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The kidney plays a major role in maintaining proper serum phosphate concentrations through mechanisms that are not completely understood. The identification of genes causing rare, heritable disorders of impaired phosphate regulation provides an opportunity to discover novel renal pathways that control mineral ion balance. We recently identified the gene causing ADHR as FGF23, which encodes a novel, secreted protein that shares 25 to 35 % homology with the fibroblast growth factor (FGF) family. However, the molecular targets of FGF23 is unknown. Several mammalian renal Na^+ -dependent Pi cotranspoters have recently been isolated and characterized. The cDNAs of these transporters can be divided into three types (types I-III) in the kidney cortex. It has been demonstrated that the type II transporter is a major functional Na^+ -dependent Pi cotransporter in the proximal tubules.In the present study, we identified a molecular target of FGF23. This protein is a mammalian Na/Pi-cotransporter with a high degree of homology to described type II Na/Pi-cotransporters. Expression of the mRNA and the protein of such a transport protein was demonstrated in the mammalian kidney. Kinetic properties and pH dependence of type IIc-mediated Na/Pi-cotransport favor this protein as a candidate for a Na/Pi cotransporter involved in renal Pi transport.