Department of Agricultural and Nutritional Sciences, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.
Department of Anatomy, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Kidney Int. 2018 Sep;94(3):491-501. doi: 10.1016/j.kint.2018.03.006. Epub 2018 May 31.
Fibroblast growth factor 23 (FGF23) is a proteohormone regulating renal phosphate transport and vitamin D metabolism as well as inducing left heart hypertrophy. FGF23-deficient mice suffer from severe tissue calcification, accelerated aging and a myriad of aging-associated diseases. Bone cells produce FGF23 upon store-operated calcium ion entry (SOCE) through the calcium selective ion channel Orai1. AMP-activated kinase (AMPK) is a powerful energy sensor helping cells survive states of energy deficiency, and AMPK down-regulates Orai1. Here we investigated the role of AMPK in FGF23 production. Fgf23 gene transcription was analyzed by qRT-PCR and SOCE by fluorescence optics in UMR106 osteoblast-like cells while the serum FGF23 concentration and phosphate metabolism were assessed in AMPKα1-knockout and wild-type mice. The AMPK activator, 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) down-regulated, whereas the AMPK inhibitor, dorsomorphin dihydrochloride (compound C) and AMPK gene silencing induced Fgf23 transcription. AICAR decreased membrane abundance of Orai1 and SOCE. SOCE inhibitors lowered Fgf23 gene expression induced by AMPK inhibition. AMPKα1-knockout mice had a higher serum FGF23 concentration compared to wild-type mice. Thus, AMPK participates in the regulation of FGF23 production in vitro and in vivo. The inhibitory effect of AMPK on FGF23 production is at least in part mediated by Orai1-involving SOCE.
成纤维细胞生长因子 23（FGF23）是一种调节肾脏磷酸盐转运和维生素 D 代谢以及诱导左心肥厚的蛋白激素。缺乏 FGF23 的小鼠患有严重的组织钙化、加速衰老和多种与衰老相关的疾病。当通过钙选择性离子通道 Orai1 进行储存操作的钙离子内流（SOCE）时，骨细胞会产生 FGF23。 AMP 激活的蛋白激酶（AMPK）是一种强大的能量传感器，有助于细胞在能量缺乏状态下存活，并且 AMPK 下调 Orai1。在这里，我们研究了 AMPK 在 FGF23 产生中的作用。通过 qRT-PCR 分析 UMR106 成骨样细胞中的 Fgf23 基因转录，通过荧光光学分析 SOCE，同时评估 AMPKα1 敲除和野生型小鼠中的血清 FGF23 浓度和磷酸盐代谢。AMPK 激活剂 5-氨基咪唑-4-甲酰胺核糖核苷酸（AICAR）下调，而 AMPK 抑制剂双盐酸多莫林（化合物 C）和 AMPK 基因沉默诱导 Fgf23 转录。AICAR 降低了 Orai1 和 SOCE 的膜丰度。SOCE 抑制剂降低了 AMPK 抑制诱导的 Fgf23 基因表达。与野生型小鼠相比，AMPKα1 敲除小鼠的血清 FGF23 浓度更高。因此，AMPK 参与了体外和体内 FGF23 产生的调节。AMPK 对 FGF23 产生的抑制作用至少部分是通过涉及 Orai1 的 SOCE 介导的。
