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

肾脏在维持适当的血清磷酸盐浓度中起主要作用，其机制尚不完全清楚。鉴定导致磷酸盐调节受损的罕见遗传性疾病的基因为发现控制矿物质离子平衡的新肾途径提供了机会。我们最近确定了引起ADHR的基因为FGF23，该基因编码一种新的分泌蛋白，与成纤维细胞生长因子（FGF）家族具有25%至35%的同源性。然而，FGF23的分子靶点尚不清楚。几种哺乳动物肾Na^+依赖的Pi协转座子最近被分离和表征。这些转运体的cdna在肾皮质中可分为三种类型（I-III型）。已经证明，II型转运蛋白是近端小管中主要的功能性Na^+依赖Pi共转运蛋白。在本研究中，我们确定了FGF23的一个分子靶点。该蛋白是一种哺乳动物Na/ pi共转运蛋白，与II型Na/ pi共转运蛋白高度同源。在哺乳动物肾脏中证实了这种转运蛋白的mRNA和蛋白的表达。ii型ic介导的Na/Pi共转运的动力学性质和pH依赖性使该蛋白成为参与肾Pi转运的Na/Pi共转运蛋白的候选蛋白。

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.