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首页> 外文期刊>Archives of Toxicology >Indoxyl sulfate enhances IL-1 beta-induced E-selectin expression in endothelial cells in acute kidney injury by the ROS/MAPKs/NF kappa B/AP-1 pathway
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Indoxyl sulfate enhances IL-1 beta-induced E-selectin expression in endothelial cells in acute kidney injury by the ROS/MAPKs/NF kappa B/AP-1 pathway

机译：硫酸吲哚酚通过ROS / MAPKs / NF kappa B / AP-1途径增强IL-1β诱导的急性肾损伤内皮细胞中E选择素的表达

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Uremic toxins are considered a risk factor for cardiovascular disorders in kidney diseases, but it is not known whether, under inflammatory conditions, they affect adhesion molecule expression on endothelial cells, which may play a critical role in acute kidney injury (AKI). In the present study, in cardiovascular surgery-related AKI patients, who are known to have high plasma levels of the uremic toxin indoxyl sulfate (IS), plasma levels of IL-1 beta were found to be positively correlated with plasma levels of the adhesion molecule E-selectin. In addition, high E-selectin and IL-1 beta expression were seen in the kidney of ischemia/reperfusion mice in vivo. We also examined the effects of IS on E-selectin expression by IL-1 beta-treated human umbilical vein endothelial cells (HUVECs) and the underlying mechanism. IS pretreatment of HUVECs significantly increased IL-1 beta-induced E-selectin expression, monocyte adhesion, and the phosphorylation of mitogen-activated protein kinases (ERK, p38, and JNK) and transcription factors (NF-kappa B and AP-1), and phosphorylation was decreased by pretreatment with inhibitors of ERK1/2 (PD98059), p38 MAPK (SB202190), and JNK (SP600125). Furthermore, IS increased IL-1 beta-induced reactive oxygen species (ROS) production and this effect was inhibited by pretreatment with N-acetylcysteine (a ROS scavenger) or apocynin (a NADPH oxidase inhibitor). Gel shift assays and ChIP-PCR demonstrated that IS enhanced E-selectin expression in IL-1-treated HUVECs by increasing NF-kappa B and AP-1 DNA-binding activities. Moreover, IS-enhanced E-selectin expression in IL-1 beta-treated HUVECs was inhibited by Bay11-7082, a NF-kappa B inhibitor. Thus, IS may play an important role in the development of cardiovascular disorders in kidney diseases during inflammation by increasing endothelial expression of E-selectin.
机译：尿毒症毒素被认为是肾脏疾病中心血管疾病的危险因素，但尚不清楚在炎性条件下它们是否影响内皮细胞上粘附分子的表达，这可能在急性肾损伤（AKI）中起关键作用。在本研究中，在心血管外科相关的AKI患者中，血浆血浆中的尿毒症毒素吲哚酚硫酸盐（IS）含量较高，血浆IL-1β水平与血浆血浆黏附水平呈正相关分子E-选择素。另外，在体内缺血/再灌注小鼠的肾脏中观察到高的E-选择蛋白和IL-1β表达。我们还检查了IL对IL-1β处理的人脐静脉内皮细胞（HUVEC）对E-选择素表达的影响及其潜在机制。 IS对HUVEC的预处理显着增加了IL-1β诱导的E-选择素表达，单核细胞粘附以及促分裂原活化蛋白激酶（ERK，p38和JNK）和转录因子（NF-κB和AP-1）的磷酸化，并通过ERK1 / 2（PD98059），p38 MAPK（SB202190）和JNK（SP600125）抑制剂预处理来降低磷酸化。此外，IS增加了IL-1β诱导的活性氧（ROS）的产生，并且用N-乙酰半胱氨酸（ROS清除剂）或载脂蛋白（AADCynin）（NADPH氧化酶抑制剂）预处理抑制了该作用。凝胶位移分析和ChIP-PCR证明IS通过增加NF-κB和AP-1 DNA结合活性增强了经IL-1处理的HUVEC中E-选择素的表达。此外，IL-1β处理的HUVEC中IS增强的E-选择素表达被NF-κB抑制剂Bay11-7082抑制。因此，IS可能通过增加E-选择蛋白的内皮表达而在炎症期间肾脏疾病的心血管疾病的发展中起重要作用。

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