Tumor necrosis factor stimulates fibroblast growth factor 23 levels in chronic kidney disease and non-renal inflammation
Tumor necrosis factor stimulates fibroblast growth factor 23 levels in chronic kidney disease and non-renal inflammation
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DOI：
10.1016/j.kint.2019.04.009
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发表时间：
2019-10-01
影响因子：
19.6
通讯作者：
Wagner, Carsten A.
中科院分区：
文献类型：
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作者：
Egli-Spichtig, Daniela;Silva, Pedro Henrique Imenez;Wagner, Carsten A.
成纤维细胞生长因子23（FGF23）调节磷酸盐稳态，其在慢性肾脏疾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疾病的特征，并且与血浆FGF 23的增加有关，我们检查了炎症是否直接刺激FGF 23。在基于人群的队列中，血浆肿瘤坏死因子（TNF）是唯一与血浆FGF 23独立正相关的炎性细胞因子。慢性肾脏疾病的小鼠模型显示肾脏炎症、肾脏FGF 23表达和升高的全身FGF 23水平的迹象。肾脏FGF23的表达与孤儿核受体Nurr1在其他器官中调节FGF23的表达一致。抗体介导的TNF中和使血浆FGF23正常化并抑制异位肾FGF23表达。相反，对照小鼠的TNF给药增加了血浆FGF23而不改变血浆磷酸盐。此外，在患有炎性肠病和正常肾功能的IL 10缺陷小鼠中，血浆FGF 23升高，并在TNF中和后正常化。因此，炎性细胞因子TNF有助于升高的系统性FGF 23水平，并且还在慢性肾病的动物模型中触发异位肾Fgf23表达。
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.