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

肾脏通过尚未完全了解的机制在维持适当的血磷浓度方面起主要作用。磷酸盐调节受损的罕见遗传性疾病基因的识别为发现控制矿物质离子平衡的新的肾脏途径提供了机会。我们最近确定导致ADHR的基因是FGF23，它编码一种新的分泌蛋白，与成纤维细胞生长因子(FGF)家族有25%至35%的同源性。然而，FGF23的分子靶点尚不清楚。最近分离并鉴定了几种哺乳动物肾脏钠离子依赖的PI共转座子。这些转运蛋白的cDNA在肾皮质中可分为三种类型(类型I-III)。研究表明，II型转运蛋白是近端肾小管上皮细胞主要的钠离子依赖的PI辅助转运蛋白，本研究确定了FGF23的一个分子靶点。该蛋白是一种哺乳动物的Na/PI共转运蛋白，与所描述的II型Na/PI共转运蛋白具有高度的同源性。这种转运蛋白的mRNA和蛋白在哺乳动物肾脏中得到了表达。IIc介导的Na/PI共转运的动力学性质和pH依赖性有利于该蛋白作为参与肾脏PI转运的Na/PI共转运蛋白的候选者。

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.