Fibroblast growth factor 23 in renal phosphate reabsorption and vitamin D metabolism

成纤维细胞生长因子 23 在肾脏磷酸盐重吸收和维生素 D 代谢中的作用

• 批准号: 14370320
• 负责人: MIYAMOTO Kenichi
• 金额: $ 9.09万
• 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: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370320/
• 关键词: FGF23; phosphate; kidney; phosphatonin; receptor; Brain

Fibroblast growth factor 23 (FGF23), a phosphaturic factor, is involved in the regulation of renal Pi reabsocption. Proteolysis-resistant FGF23 mutants expressed in rodents reduce Pi uptake in both intestine and kidney, independent of parathyroid hormone action. In the present study, we investigated whether FGF23 affect dietary regulation of Na^+-dependent Pi (Na/Pi) cotransport in rat kidney using wild-type FGF23 and an R 179Q mutant, which disrupts a consensus proteolytic cleavage motifRats injected with naked human FGF23 DNA (wild type or R 179Q mutant) expressed human FGF23 transcript in the liver. In those animals, the plasma calcium and parathyroid hormone levels were not affected by FGF23 (either wild type or R179Q mutant). FGF23-R179Q did, however, significantly decrease the plasma Pi and renal Na/Pi cotransport activity and also the levels of type IIc Na/Pi cotransporter proteins in BBMVs from normal rat kidney. In rats fed a low Pi diet, the levels of type IIa and type IIc Na/Pi cotransporters were markedly ink in Western blotting and immunohistochemical analyses. After injection of FGF23-R 179Q DNA into the rats fed a low Pi diet, the levels of the type IIa and type IIc transporter proteins were decreased. Thus FGF23 mutant blunts the signaling of Pi deprivation in renal type II Na/Pi cotransporters, suggesting that the FGF23 pathway could be involved in the signaling of dietary Pi

成纤维细胞生长因子23(FGF23)是一种磷酸因子，参与了肾脏PI再摄取的调节。在啮齿动物中表达的抗蛋白水解性FGF23突变体减少了肠道和肾脏对PI的摄取，这与甲状旁腺激素的作用无关。在本研究中，我们使用野生型FGF23和一个R179Q突变体来研究FGF23是否影响饮食对大鼠肾脏Na+依赖的PI(Na/PI)共转运的调节，该突变体破坏了公认的蛋白水解性切割基序，即注射裸露人FGF23 DNA(野生型或R179Q突变体)的大鼠在肝脏表达人FGF23转录本。在这些动物中，血浆钙和甲状旁腺激素水平不受FGF23(野生型或R179Q突变体)的影响。但FGF23-R179Q可显著降低正常大鼠肾脏BBMV的血浆PI和肾脏Na/PI共转运蛋白活性及IIc Na/PI共转运蛋白水平。Western blotting和免疫组织化学分析显示，低PI饲料喂养的大鼠脑内IIa型和IIc型Na/PI共转运蛋白的表达水平明显下降。低磷饲料大鼠注射FGF23-R179Q DNA后，IIa和IIc型转运蛋白水平降低。因此，FGF23突变体减弱了肾脏II型Na/PI共转运体中PI缺乏的信号，提示FGF23通路可能参与了膳食PI的信号转导

项目成果

Saito H, Kusano K, Kinosaki M, Ito H, Hirata M, Segawa H, Miyamoto K, Fukushima N.: "Human fibroblast growth factor-23 mutants suppress Na+-dependent phosphate co-transport activity and 1 α, 25dihydroxyvitamin D3 production"J Biol Chem. 278. 2206-2211 (20

Saito H、Kusano K、Kinosaki M、Ito H、Hirata M、Sekawa H、Miyamoto K、Fukushima N.：“人成纤维细胞生长因子-23 突变体抑制 Na+ 依赖性磷酸盐共转运活性和 1 α, 25 二羟基维生素 D3 的产生”生物化学杂志 278。2206-2211 (20

Segawa H.: "Growth-related renal type II Na/Pi contransporter"J Biol Chem. 277. 19665-19672 (2002)

Sekawa H.：“生​​长相关的肾 II 型 Na/Pi 转运蛋白”J Biol Chem。

Ohkido I, Segawa H, Yanagida R, Nakamura M, Miyamoto K.: "Cloning, gene structure and dietary regulation of the type-IIc Na/Pi cotransporter in the mouse kidney"Pflugers Arch.2003 Apr. 446(1). 106-115 (2003)

Ohkido I、Sekawa H、Yanagida R、Nakamura M、Miyamoto K.：“小鼠肾脏中 IIc 型 Na/Pi 协同转运蛋白的克隆、基因结构和饮食调节”Pflugers Arch.2003 Apr. 446(1)。

桑波田 雅士: "リン代謝の最近の理解とリン調節薬の将来、透析療法ネクストII透析骨症は防げる"43-48 (2003)

Masashi Kuwabata：“磷代谢的最新认识和磷调节药物的未来，透析疗法 NEXT II 透析骨病是可以预防的”43-48 (2003)

Segawa H, Kawakami E, Kaneko I, Kuwahata M, Ito M, Kusano K, Saito H, Fukushima N, Miyamoto K.: "Effect of hydrolysis-resistant FGF23-R179Q on dietary phosphate regulation of the renal type-II Na/Pi transporter"Pflugers Arch-Eur J Physiol. 446. 585-592 (2

Sekawa H、Kawakami E、Kaneko I、Kuwahata M、Ito M、Kusano K、Saito H、Fukushima N、Miyamoto K.：“抗水解 FGF23-R179Q 对 II 型肾 Na/Pi 膳食磷酸盐调节的影响