Local activation of interleukin 6 signaling is associated with arteriovenous fistula stenosis in hemodialysis patients
Local activation of interleukin 6 signaling is associated with arteriovenous fistula stenosis in hemodialysis patients
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DOI：
10.1053/j.ajkd.2007.02.266
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发表时间：
2007-05-01
影响因子：
13.2
通讯作者：
Grandaliano, Giuseppe
中科院分区：
文献类型：
--
作者：
Marrone, Daniela;Pertosa, Giovanni;Grandaliano, Giuseppe
背景：血管通路失败是血液透析患者发病的主要原因。动静脉瘘狭窄（AVF）在组织学上与动脉粥样硬化相似。最近的研究表明，白细胞介素6 （IL-6）通过结合2种特异性受体gp80和gp130在动脉粥样硬化的发病过程中起关键作用。gp130被激活后，会与酪氨酸激酶Janus激酶（JAK2）相互作用，进而激活转录因子、信号转导和转录激活因子（STAT3），直接开启几种促炎基因。本研究的目的是评估狭窄性avf中gp130的表达和JAK2/STAT3的激活。方法：选取44例行AVF形成手术的患者；其中10例AVF衰竭，组织学证实AVF狭窄（壁腔比bb0.1）。在血管通路的创建和修复过程中收集了avf的静脉碎片。通过共聚焦显微镜观察gp130和gp80的表达以及JAK/STAT的激活情况。在AVF创建和改良时分离外周血单个核细胞。结果：原生avf中几乎检测不到的gp130蛋白表达在狭窄avf的静脉分支中显著增加。IL-6受体的信号亚基与IL-6结合亚基gp80广泛共定位。表达gp-130的细胞主要为CD34(+)，提示该受体主要由新生血管内皮细胞表达。同时，在狭窄性avf内皮细胞中观察到JAK2/STAT3的磷酸化水平显著升高。有趣的是，在AVF失败时分离的外周血单个核细胞与透析年龄匹配的对照组相比，IL-6表达显著增加。结论：IL-6受体激活可能在血液透析患者AVF衰竭的发病机制中起作用，并可能是一种潜在的治疗靶点。
Background: Vascular access failure is the main cause of morbidity in hemodialysis patients. Stenosis of the arteriovenous fistula (AVF) is similar histologically to atherosclerosis. Recent studies showed that interleukin 6 (IL-6) has a key role in the pathogenesis of atherosclerosis by binding 2 specific receptors, gp80 and gp130. When activated, gp130 interacts with a tyrosine kinase, Janus kinase (JAK2), which then activates a transcription factor, signal transducers and activators of transcription (STAT3), directly turning on several proinflammatory genes. The aim of this study is to evaluate gp130 expression and JAK2/STAT3 activation within stenotic AVFs.Methods: 44 patients undergoing surgery for AVF creation were enrolled; 10 of them had AVF failure with histologically proven AVF stenosis (wall-lumen ratio > 1). A venous fragment of the AVFs was collected during creation and revision of the vascular access. gp130 and gp80 expression, as well as JAK/STAT activation, were evaluated by means of confocal microscopy. Peripheral-blood mononuclear cells were isolated at the time of AVF creation and revision.Results: gp130 protein expression, barely detectable in native AVFs, was strikingly increased within the venous branch of stenotic AVFs. The signaling subunit of the IL-6 receptor broadly colocalized with gp80, the IL-6-binding subunit. gp-130-expressing cells were mainly CD34(+), suggesting that this receptor is expressed primarily by neovasculature endothelial cells. At the same time, a significant increase in phosphorylation of JAK2/STAT3 was observed in endothelial cells of stenotic AVFs. Interestingly, peripheral-blood mononuclear cells isolated at the time of AVF failure presented strikingly greater IL-6 expression compared with dialysis age-matched controls.Conclusion: IL-6 receptor activation may have a role in the pathogenesis of AVF failure in hemodialysis patients and may represent a potential therapeutic target in this setting.