Institute of Physiology, University of Zurich, Zurich, Switzerland; Swiss National Center of Competence in Research NCCR-Kidney.CH, University of Zurich, Zurich, Switzerland; Department of Pediatrics, Division of Nephrology, University of California, San Francisco, San Francisco, California, USA.
Institute of Physiology, University of Zurich, Zurich, Switzerland; Swiss National Center of Competence in Research NCCR-Kidney.CH, University of Zurich, Zurich, Switzerland.
Kidney Int. 2019 Oct;96(4):890-905. doi: 10.1016/j.kint.2019.04.009. Epub 2019 May 14.
Fibroblast growth factor 23 (FGF23) regulates phosphate homeostasis, and its early rise in patients with chronic kidney disease is independently associated with all-cause mortality. Since inflammation is characteristic of chronic kidney disease and associates with increased plasma FGF23 we examined whether inflammation directly stimulates FGF23. In a population-based cohort, plasma tumor necrosis factor (TNF) was the only inflammatory cytokine that independently and positively correlated with plasma FGF23. Mouse models of chronic kidney disease showed signs of renal inflammation, renal FGF23 expression and elevated systemic FGF23 levels. Renal FGF23 expression coincided with expression of the orphan nuclear receptor Nurr1 regulating FGF23 in other organs. Antibody-mediated neutralization of TNF normalized plasma FGF23 and suppressed ectopic renal Fgf23 expression. Conversely, TNF administration to control mice increased plasma FGF23 without altering plasma phosphate. Moreover, in Il10-deficient mice with inflammatory bowel disease and normal kidney function, plasma FGF23 was elevated and normalized upon TNF neutralization. Thus, the inflammatory cytokine TNF contributes to elevated systemic FGF23 levels and also triggers ectopic renal Fgf23 expression in animal models of chronic kidney disease.
成纤维细胞生长因子 23（FGF23）调节磷酸盐稳态，其在慢性肾脏病患者中的早期升高与全因死亡率独立相关。由于炎症是慢性肾脏病的特征，并与血浆 FGF23 增加相关，我们研究了炎症是否直接刺激 FGF23。在一项基于人群的队列研究中，血浆肿瘤坏死因子（TNF）是唯一与血浆 FGF23 独立且呈正相关的炎症细胞因子。慢性肾脏病的小鼠模型显示出肾脏炎症、肾脏 FGF23 表达和全身 FGF23 水平升高的迹象。肾脏 FGF23 的表达与调节其他器官 FGF23 的孤儿核受体 Nurr1 的表达相吻合。TNF 的抗体中和作用使血浆 FGF23 正常化并抑制异位肾脏 Fgf23 表达。相反，给予对照小鼠 TNF 可增加血浆 FGF23，而不改变血浆磷酸盐。此外，在具有炎症性肠病和正常肾功能的 Il10 缺陷型小鼠中，血浆 FGF23 升高，并在 TNF 中和后恢复正常。因此，炎症细胞因子 TNF 导致全身性 FGF23 水平升高，并在慢性肾脏病的动物模型中触发异位肾脏 Fgf23 表达。
