Indoxyl Sulfate Induces Leukocyte-Endothelial Interactions through Up-regulation of E-selectin
Indoxyl Sulfate Induces Leukocyte-Endothelial Interactions through Up-regulation of E-selectin
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DOI：
10.1074/jbc.m110.166686
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发表时间：
2010-12-01
影响因子：
4.8
通讯作者：
Yoshida, Masayuki
中科院分区：
文献类型：
--
作者：
Ito, Shunsuke;Osaka, Mizuko;Yoshida, Masayuki
尽管慢性肾脏疾病和动脉粥样硬化之间存在正相关，但尿毒症毒素在白细胞-内皮相互作用中的致病作用尚未报道。因此，我们研究了硫酸吲哚酚（一种尿毒症毒素）对白细胞与活化内皮细胞粘附的影响及其机制。用硫酸吲哚酚预处理人脐静脉内皮细胞（HUVEC）显著增强了人单核细胞（THP-1细胞系）在生理流动条件下与TNF-α激活的HUVEC的粘附。用硫酸吲哚酚处理增强HUVEC中E-选择素的表达水平，但不增强ICAM-1或VCAM-1的表达水平。硫酸吲哚酚处理增强了TNF-α激活的HUVEC中JNK、p38 MAPK和NF-κ B的激活。JNK和NF-κ B的抑制剂减弱了硫酸吲哚酚诱导的HUVEC中E-选择素的表达和随后的THP-1粘附。此外，用NAD（P）H氧化酶抑制剂夹竹桃苷和谷胱甘肽供体N-乙酰半胱氨酸处理抑制硫酸吲哚酚诱导的THP-1与HUVEC粘附的增强。接下来，我们检查了硫酸吲哚酚在肾切除的慢性肾病模型小鼠中的体内作用。硫酸吲哚酚诱导的白细胞粘附到股动脉显着减少抗E-选择素抗体治疗。这些发现表明，硫酸吲哚酚通过上调E-选择素，可能是通过JNK和NF-κ B依赖性途径增强白细胞-内皮细胞相互作用。
Despite a positive correlation between chronic kidney disease and atherosclerosis, the causative role of uremic toxins in leukocyte-endothelial interactions has not been reported. We thus examined the effects of indoxyl sulfate, a uremic toxin, on leukocyte adhesion to activated endothelial cells and the underlying mechanisms. Pretreatment of human umbilical vein endothelial cells (HUVEC) with indoxyl sulfate significantly enhanced the adhesion of human monocytic cells (THP-1 cell line) to TNF-alpha-activated HUVEC under physiological flow conditions. Treatment with indoxyl sulfate enhanced the expression level of E-selectin, but not that of ICAM-1 or VCAM-1, in HUVEC. Indoxyl sulfate treatment enhanced the activation of JNK, p38 MAPK, and NF-kappa B in TNF-alpha-activated HUVEC. Inhibitors of JNK and NF-kappa B attenuated indoxyl sulfate-induced E-selectin expression in HUVEC and subsequent THP-1 adhesion. Furthermore, treatment with the NAD(P)H oxidase inhibitor apocynin and the glutathione donor N-acetylcysteine inhibited indoxyl sulfate-induced enhancement of THP-1 adhesion to HUVEC. Next, we examined the in vivo effect of indoxyl sulfate in nephrectomized chronic kidney disease model mice. Indoxyl sulfate-induced leukocyte adhesion to the femoral artery was significantly reduced by anti-E-selectin antibody treatment. These findings suggest that indoxyl sulfate enhances leukocyte-endothelial interactions through up-regulation of E-selectin, presumably via the JNK- and NF-kappa B-dependent pathway.