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

哺乳动物肾脏中调节磷酸盐信号网络的分子的鉴定

基本信息

批准号：
12470211
负责人：
MIYAMOTO Ken-ichi
金额：
$ 9.47万
依托单位：
The University of Tokushima
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

项目摘要

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.

肾脏通过尚不完全清楚的机制在维持适当的血清磷酸盐浓度方面起着重要作用。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离子平衡的新肾脏途径提供了机会。我们最近鉴定了引起ADHR的基因为FGF 23，其编码一种与成纤维细胞生长因子（FGF）家族具有25 - 35%同源性的新型分泌蛋白。然而，FGF 23的分子靶点是未知的。最近分离并鉴定了几种哺乳动物肾Na^+依赖性Pi共转运体。这些转运蛋白的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Na^+依赖性Pi协同转运蛋白，在本研究中，我们确定了FGF 23的分子靶点。该蛋白是哺乳动物Na/Pi共转运蛋白，与所述II型Na/Pi共转运蛋白具有高度同源性。这种转运蛋白的mRNA和蛋白质的表达在哺乳动物肾脏中得到证实。IIc型介导的Na/Pi共转运的动力学特性和pH依赖性有利于这种蛋白质作为参与肾Pi转运的Na/Pi共转运蛋白的候选者。