We assessed the involvement of fibroblast growth factor 23 (FGF23) in phosphaturia in sickle cell disease (SCD) mice. Control and SCD mice were treated with FGF23 neutralizing antibody (FGF23Ab) for 24 hours. Serum ferritin was significantly increased in SCD mice and was significantly reduced in female but not male SCD mice by FGF23Ab. FGF23Ab significantly reduced increased erythropoietin in SCD kidneys. Serum intact FGF23 was significantly increased in SCD female mice and was markedly increased in SCD male mice; however, FGF23Ab significantly reduced serum intact FGF23 in both genotypes and sexes. Serum carboxy-terminal-fragment FGF23 (cFGF23) was significantly reduced in SCD IgG male mice and was markedly but not significantly reduced in SCD IgG female mice. FGF23Ab significantly increased cFGF23 in both sexes and genotypes. Serum 1,25-dihydroxyvitamin D3 was significantly increased in SCD IgG and was further significantly increased by FGF23Ab in both sexes and genotypes. Significantly increased blood urea nitrogen in SCD was not reduced by FGF23Ab. The urine phosphate (Pi)/creatinine ratio was significantly increased in SCD in both sexes and was significantly reduced by FGF23Ab. Increased SCD kidney damage marker kidney injury molecule 1 was rescued, but sclerotic glomeruli, increased macrophages, and lymphocytes were not rescued by short-term FGF23Ab. FGF23Ab significantly reduced increased phospho-fibroblast growth factor receptor 1, αKlotho, phosphorylated extracellular signal-regulated kinase, phosphorylated serum/glucocorticoid-regulated kinase 1, phosphorylated sodium-hydrogen exchanger regulatory factor-1, phosphorylated janus kinase 3, and phosphorylated transducer and activator of transcription-3 in SCD kidneys. The type II sodium Pi cotransporter (NPT2a) and sodium-dependent Pi transporter PiT-2 proteins were significantly reduced in SCD kidneys and were increased by FGF23Ab. We conclude that increased FGF23/FGF receptor 1/αKlotho signaling promotes Pi wasting in SCD by downregulating NPT2a and PIT2 via modulation of multiple signaling pathways that could be rescued by FGF23Ab.

中文翻译：

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成纤维细胞生长因子 23 中和抗体可改善镰状细胞病小鼠肾磷酸处理异常。

我们评估了成纤维细胞生长因子 23 (FGF23) 在镰状细胞病 (SCD) 小鼠磷酸尿中的作用。用 FGF23 中和抗体 (FGF23Ab) 处理对照和 SCD 小鼠 24 小时。FGF23Ab 使 SCD 小鼠的血清铁蛋白显着增加，而雌性而非雄性 SCD 小鼠的血清铁蛋白显着降低。FGF23Ab 显着降低 SCD 肾脏中增加的红细胞生成素。血清完整FGF23在SCD雌性小鼠中显着升高，在SCD雄性小鼠中显着升高；然而，FGF23Ab 显着降低基因型和性别的血清完整 FGF23。SCD IgG 雄性小鼠中血清羧基末端片段 FGF23 (cFGF23) 显着降低，而 SCD IgG 雌性小鼠中血清羧基末端片段 FGF23 (cFGF23) 显着但不显着降低。FGF23Ab 显着增加性别和基因型的 cFGF23。无论性别还是基因型，SCD IgG 中的血清 1,25-二羟基维生素 D3 均显着增加，并且 FGF23Ab 进一步显着增加血清 1,25-二羟基维生素 D3。FGF23Ab 不会降低 SCD 中显着增加的血尿素氮。两性 SCD 患者的尿磷酸盐 (Pi)/肌酐比值均显着升高，而 FGF23Ab 则显着降低尿磷酸盐 (Pi)/肌酐比值。增加的SCD肾损伤标志物肾损伤分子1被挽救，但硬化的肾小球、增加的巨噬细胞和淋巴细胞未被短期FGF23Ab挽救。FGF23Ab 显着减少增加的磷酸化成纤维细胞生长因子受体 1、αKlotho、磷酸化细胞外信号调节激酶、磷酸化血清/糖皮质激素调节激酶 1、磷酸化钠氢交换器调节因子 1、磷酸化 janus 激酶 3 以及磷酸化转导器和激活剂SCD 肾脏中转录 3 的表达。SCD 肾脏中 II 型钠 Pi 协同转运蛋白 (NPT2a) 和钠依赖性 Pi 转运蛋白 PiT-2 蛋白显着减少，而 FGF23Ab 则增加。我们得出的结论是，FGF23/FGF 受体 1/αKlotho 信号传导增加，通过调节 FGF23Ab 可以挽救的多种信号传导途径，下调 NPT2a 和 PIT2，从而促进 SCD 中的 Pi 消耗。