The inflammation-lipocalin 2 axis may contribute to the development of chronic kidney disease
The inflammation-lipocalin 2 axis may contribute to the development of chronic kidney disease
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DOI：
10.1093/ndt/gft449
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发表时间：
2014-03-01
影响因子：
6.1
通讯作者：
Nishimura, Fusanori
中科院分区：
文献类型：
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作者：
Hashikata, Atsushi;Yamashita, Akiko;Nishimura, Fusanori
背景慢性肾脏病（chronic kidney disease，CKD）是冠心病的一个重要危险因素，既往研究表明慢性肾脏病的发病机制中存在低度炎症反应。本研究旨在（i）鉴定和确认与内毒素刺激的巨噬细胞共培养的系膜细胞中上调的基因及其产物;（ii）通过流行病学方法确定炎症条件下系膜细胞中上调的基因和蛋白质的临床相关性。DNA微阵列分析显示许多基因及其产物的表达上调，包括几种细胞因子和趋化因子，以及炎症标志物脂质运载蛋白2基因。脂质运载蛋白2的基因表达和蛋白上调受到内毒素和肿瘤坏死因子（TNF）-α刺激的协同影响。在人体研究中，脂质运载蛋白2水平与肌酐显著相关（r = 0.419，P < 0.001），与eGFR呈负相关（r =-0.365，P < 0.001）。多因素Logistic回归分析显示，在420例定期体检的普通人群中，脂质运载蛋白2与可溶性肿瘤坏死因子受体2（sTNF-R2）、eGFR和尿酸水平显著相关。当从分析中排除糖尿病患者时，脂质运载蛋白2仍然与sTNF-R2、eGFR和尿酸相关。由于活化的TNF系统，如升高的sTNF-R2所示，以及升高的尿酸最近与升高的CKD风险有关，因此我们得出结论，炎症可能在CKD的发病机制中起重要作用，并且脂质运载蛋白2是肾功能受损的潜在通用标志物。此外，通过目前的微阵列分析获得的结果可以提高与炎症条件下CKD的病理生理学相关的基因谱的理解。
Background. Chronic kidney disease (CKD) is an important risk factor for coronary heart disease, and previous studies indicated the involvement of low-grade inflammation in the pathogenesis of CKD.Methods. The study was designed to (i) identify and confirm genes and their products upregulated in mesangial cells cocultured with endotoxin-stimulated macrophages and (ii) determine the clinical relevance of genes and proteins upregulated in mesangial cells under inflammatory conditions by an epidemiological approach.Results. DNA microarray analysis revealed upregulated expression of many genes and their products including several cytokines and chemokines, as well as the inflammatory marker, lipocalin 2 gene. The gene expression and protein upregulation of lipocalin 2 were synergistically affected by endotoxin and tumor necrosis factor (TNF)-alpha stimulation. In human studies, lipocalin 2 level was significantly associated with creatinine (r = 0.419, P < 0.001) and negatively associated with eGFR (r = -0.365, P < 0.001). Multiple logistic regression analysis revealed a significant association between lipocalin 2 and soluble tumor necrosis factor receptor 2 (sTNF-R2), eGFR and uric acid in general subjects attending regular annual medical check-up (n = 420). When subjects with diabetes were excluded from the analysis, lipocalin 2 remained associated with sTNF-R2, eGFR and uric acid.Conclusions. Since an activated TNF system, as demonstrated by elevated sTNF-R2, and elevated uric acid were recently implicated in an elevated CKD risk, we conclude that inflammation could play an important role in the pathogenesis of CKD, and that lipocalin 2 is a potential universal marker for impaired kidney function. Furthermore, the results obtained by the current microarray analysis could improve the understanding of gene profiles associated with the pathophysiology of CKD under inflammatory conditions.