Department of Advanced Medicine for Uremia, Nagoya University School of Medicine, Aichi, Japan.
Life Sci. 2012 Sep 4;91(5-6):172-7. doi: 10.1016/j.lfs.2012.06.033. Epub 2012 Jul 7.
Indoxyl 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.
The 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.
Ang 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.
The actions of indoxyl sulfate including crosstalk with Ang II signaling may be closely involved in the pathogenesis of CKD associated with arteriosclerosis.
硫酸吲哚酚是一种尿毒症毒素，被认为是慢性肾脏病（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（VSMCs）中血小板衍生生长因子（PDGF）信号的串扰。本研究检查硫酸吲哚酚是否增强血管紧张素 II（Ang II）信号，因为 CKD 患者的血清 Ang II 水平升高。
使用 VSMCs 确定硫酸吲哚酚和 Ang II 对 ERK 和表皮生长因子受体（EGFR）磷酸化以及迁移的影响。使用不仅 VSMCs 而且还使用正常、尿毒症和硫酸吲哚酚给药的尿毒症大鼠的动脉来确定 EGFR 的表达。
即使在 Ang II 刺激期间没有硫酸吲哚酚，硫酸吲哚酚预先孵育 24 小时也会增强 Ang II 依赖性 ERK 和 EGFR 磷酸化以及 VSMCs 的迁移。在硫酸吲哚酚刺激的培养 VSMCs 中，EGFR 的表达增加。在大鼠动脉 VSMCs 中，血清硫酸吲哚酚水平反映了 EGFR 的表达水平。抗氧化剂 N-乙酰半胱氨酸可抑制硫酸吲哚酚上调 EGFR 的表达。EGFR 抑制剂 AG1478 抑制硫酸吲哚酚增强 Ang II 诱导的细胞效应。总之，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。
硫酸吲哚酚的作用包括与 Ang II 信号的串扰可能与 CKD 相关的动脉硬化的发病机制密切相关。
