Indoxyl sulfate enhances angiotensin II signaling through upregulation of epidermal growth factor receptor expression in vascular smooth muscle cells.
Indoxyl sulfate enhances angiotensin II signaling through upregulation of epidermal growth factor receptor expression in vascular smooth muscle cells.
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Indoxylsulfate 通过上调血管平滑肌细胞中表皮生长因子受体的表达来增强血管紧张素 II 信号传导。
DOI：
10.1016/j.lfs.2012.06.033
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
Miyazaki H.
中科院分区：
文献类型：
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作者：
Shimizu H;Hirose Y;Goto S;Nishijima F;Zrelli H;Zghonda N;Niwa T;Miyazaki H.
AIMS硫酸吲哚酚是一种尿毒症毒素，被认为是慢性肾病 (CKD) 患者动脉硬化的危险因素。我们之前报道了硫酸吲哚酚的作用，包括与血管平滑肌细胞（VSMC）中血小板衍生生长因子（PDGF）信号传导的串扰。本研究探讨硫酸吲哚酚是否会增强血管紧张素 II (Ang II) 信号传导，因为 CKD 患者血清 Ang II 水平升高。 主要方法使用 VSMC 测定硫酸吲哚酚和 Ang II 对 ERK 和表皮生长因子受体 (EGFR) 磷酸化和迁移的影响。 EGFR 的表达不仅使用 VSMC 进行测定，还使用正常、尿毒症和硫酸吲哚酚给药的尿毒症大鼠的动脉进行测定。关键发现即使在 Ang II 刺激期间不存在硫酸吲哚酚的情况下，预先与硫酸吲哚酚孵育 24 小时也会增强 ERK 和 EGFR 的 Ang II 依赖性磷酸化以及 VSMC 的迁移。硫酸吲哚酚刺激培养的 VSMC 中 EGFR 的表达增加。在大鼠动脉VSMC中，硫酸吲哚酚的血清水平反映了EGFR的表达水平。硫酸吲哚酚上调的 EGFR 表达被抗氧化剂 N-乙酰半胱氨酸抑制。 EGFR 抑制剂 AG1478 可抑制硫酸吲哚酚增强的 Ang II 诱导的细胞效应。综上所述，这些发现表明硫酸吲哚酚通过活性氧诱导的 EGFR 表达增强 Ang II 信号传导。意义硫酸吲哚酚的作用（包括与 Ang II 信号传导的串扰）可能与动脉硬化相关 CKD 的发病机制密切相关。
AIMSIndoxyl sulfate, a uremic toxin, is considered a risk factor for arteriosclerosis in patients with chronic kidney disease (CKD). We previously reported the actions of indoxyl sulfate including crosstalk with platelet-derived growth factor (PDGF) signaling in vascular smooth muscle cells (VSMCs). The present study examines whether indoxyl sulfate enhances angiotensin II (Ang II) signaling because serum levels of Ang II are elevated in patients with CKD.MAIN METHODSThe effect of indoxyl sulfate and Ang II on phosphorylation of ERK and epidermal growth factor receptor (EGFR), and migration were determined using VSMCs. The expression of EGFR was determined using not only VSMCs but also artery of normal, uremic, and indoxyl sulfate-administrated uremic rats.KEY FINDINGSAng II-dependent phosphorylation of ERK and EGFR, and migration of VSMCs were augmented by a prior 24-h incubation with indoxyl sulfate even in the absence of indoxyl sulfate during Ang II stimulation. The expression of EGFR was increased in indoxyl sulfate-stimulated cultured VSMCs. In arterial VSMCs of rats, serum levels of indoxyl sulfate reflected the expression level of EGFR. The upregulated EGFR expression by indoxyl sulfate was suppressed by the antioxidant, N-acetylcysteine. An EGFR inhibitor, AG1478, repressed the enhancement of Ang II-induced cellular effects by indoxyl sulfate. Taken together, these findings indicate that indoxyl sulfate enhances Ang II signaling through reactive oxygen species-induced EGFR expression.SIGNIFICANCEThe actions of indoxyl sulfate including crosstalk with Ang II signaling may be closely involved in the pathogenesis of CKD associated with arteriosclerosis.