University of Copenhagen, Nephrological Department B, Herlev Hospital, Herlev, Denmark; University of Copenhagen, Nephrological Department P, Rigshospitalet, Copenhagen, Denmark.
University of Copenhagen, Nephrological Department P, Rigshospitalet, Copenhagen, Denmark.
Kidney Int. 2017 Jul;92(1):165-178. doi: 10.1016/j.kint.2017.01.015. Epub 2017 Mar 22.
Fibroblast growth factor 23 (FGF23) secreted by osteocytes is a circulating factor essential for phosphate homeostasis. High plasma FGF23 levels are associated with cardiovascular complications and mortality. Increases of plasma FGF23 in uremia antedate high levels of phosphate, suggesting a disrupted feedback regulatory loop or an extra-skeletal source of this phosphatonin. Since induction of FGF23 expression in injured organs has been reported we decided to examine the regulation of FGF23 gene and protein expressions in the kidney and whether kidney-derived FGF23 contributes to the high plasma levels of FGF23 in uremia. FGF23 mRNA was not detected in normal kidneys, but was clearly demonstrated in injured kidneys, already after four hours in obstructive nephropathy and at 8 weeks in the remnant kidney of 5/6 nephrectomized rats. No renal extraction was found in uremic rats in contrast to normal rats. Removal of the remnant kidney had no effect on plasma FGF23 levels. Well-known regulators of FGF23 expression in bone, such as parathyroid hormone, calcitriol, and inhibition of the FGF receptor by PD173074, had no impact on kidney expression of FGF23. Thus, the only direct contribution of the injured kidney to circulating FGF23 levels in uremia appears to be reduced renal extraction of bone-derived FGF23. Kidney-derived FGF23 does not generate high plasma FGF23 levels in uremia and is regulated differently than the corresponding regulation of FGF23 gene expression in bone.
成纤维细胞生长因子 23（FGF23）由骨细胞分泌，是维持磷酸盐稳态的循环因子。高血浆 FGF23 水平与心血管并发症和死亡率相关。在尿毒症中，血浆 FGF23 的增加先于磷酸盐水平升高，这表明反馈调节环路中断或这种磷酸盐素的非骨骼来源。由于已经报道了在受损器官中诱导 FGF23 表达，我们决定检查肾脏中 FGF23 基因和蛋白表达的调节，以及肾脏来源的 FGF23 是否有助于尿毒症中高血浆 FGF23 水平。正常肾脏中未检测到 FGF23 mRNA，但在受损肾脏中明显可见，在梗阻性肾病中已经在 4 小时后，在 5/6 肾切除术的残余肾脏中在 8 周时明显可见。与正常大鼠相比，尿毒症大鼠中未发现肾脏摄取。去除残余肾脏对血浆 FGF23 水平没有影响。骨中 FGF23 表达的众所周知的调节因子，如甲状旁腺激素、骨化三醇和 PD173074 抑制 FGF 受体，对肾脏 FGF23 表达没有影响。因此，受损肾脏对尿毒症中循环 FGF23 水平的唯一直接贡献似乎是减少骨源性 FGF23 的肾脏摄取。肾脏来源的 FGF23 不会在尿毒症中产生高血浆 FGF23 水平，并且其调节与骨中相应的 FGF23 基因表达调节不同。
