Spleen contributes significantly to increased circulating levels of fibroblast growth factor 23 in response to lipopolysaccharide-induced inflammation
Spleen contributes significantly to increased circulating levels of fibroblast growth factor 23 in response to lipopolysaccharide-induced inflammation
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DOI：
10.1093/ndt/gfx003
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发表时间：
2017-06-01
影响因子：
6.1
通讯作者：
Fanti, Paolo
中科院分区：
文献类型：
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作者：
Bansal, Shweta;Friedrichs, William E.;Fanti, Paolo
背景资料：成纤维细胞生长因子23（FGF 23）的循环水平逐渐增加，并与慢性肾病（CKD）的全身炎症相关。本研究的目的是确定和描述慢性肾脏病（CKD）中FGF 23与炎症之间的因果关系。方法：在健康受试者和不同水平的慢性肾脏病（CKD）患者中，循环中的FGF 23与炎症细胞因子相关。此外，在急性（一次）或慢性（2周）暴露于低剂量脂多糖（LPS）的正常小鼠中测量血液和实体器官中的FGF 23表达;慢性暴露是持续（皮下颗粒）、间歇（每日注射）或组合的持续加急性（皮下颗粒加处死当天的急性注射）。分析血液的终末（cFGF 23）和完整（iFGF 23）FGF 23水平。采用免疫组化、酶联免疫吸附试验和逆转录聚合酶链反应对实体组织进行检测。FGF 23水平与中性粒细胞明胶酶相关脂质运载蛋白显著相关（r = 0.72，P < 0.001）、C反应蛋白（r = 0.38，P < 0.001）、肿瘤坏死因子-α（r = 0.32，P = 0.001）和白细胞介素-6（r = 0.48，P < 0.001）。急性LPS给药增加了组织FGF 23 mRNA和cFGF 23的血浆水平，但不增加iFGF 23。无论是慢性持续或慢性脉动LPS增加组织或循环水平的FGF 23。然而，慢性LPS急性升高组织FGF 23 mRNA和循环cFGF 23和iFGF 23。结论：急性或慢性LPS暴露可刺激正常小鼠炎症模型产生FGF 23。我们提供的第一个证据表明，脾脏，在这些条件下，大大有助于提高循环FGF 23水平。
Background: Circulating levels of fibroblast growth factor 23 (FGF23) increase progressively and correlate with systemic inflammation in chronic kidney disease (CKD). The aim of this study was to identify and characterize the causal relationship between FGF23 and inflammation in CKD.Methods: Circulating FGF23 and inflammatory cytokines were correlated in healthy subjects and patients with varying levels of CKD. In addition, FGF23 expression in blood and solid organs was measured in normal mice that were exposed acutely (one time) or chronically (2-week) to low-dose lipopolysaccharide (LPS); chronic exposure being either sustained (subcutaneous pellets), intermittent (daily injections) or combined sustained plus acute (subcutaneous pellets plus acute injection on the day of sacrifice). Blood was analyzed for both terminal (cFGF23) and intact (iFGF23) FGF23 levels. Solid tissues were investigated with immunohistochemistry, enzyme-linked immunosorbent assay and reverse transcription polymerase chain reaction.Results: FGF23 levels correlated significantly with neutrophil gelatinase-associated lipocalin (r = 0.72, P < 0.001), C-reactive protein (r = 0.38, P < 0.001), tumor necrosis factor-alpha (r = 0.32, P = 0.001) and interleukin-6 (r = 0.48, P < 0.001). Acute LPS administration increased tissue FGF23 mRNA and plasma levels of cFGF23 but not iFGF23. Neither chronic sustained nor chronic pulsatile LPS increased the tissue or circulating levels of FGF23. However, acute on chronic LPS raised tissue FGF23 mRNA and both circulating cFG23 and iFGF23. Interestingly, the spleen was the major source of FGF23.Conclusion: Acute on chronic exposure to LPS stimulates FGF23 production in a normal mouse model of inflammation. We provide the first evidence that the spleen, under these conditions, contributes substantially to elevated circulating FGF23 levels.