Department of Medicine, St Vincent's Hospital, University of Melbourne, Fitzroy 3065, Australia.
Toxins (Basel). 2022 Jan 26;14(2):100. doi: 10.3390/toxins14020100.
The uremic toxin indoxyl sulfate (IS), elevated in chronic kidney disease (CKD), is known to contribute towards progressive cardiovascular disease. IS activates the aryl hydrocarbon receptor (AhR) mediating oxidative stress and endothelial dysfunction via activation of the CYP1A1 pathway. The present study examines AhR inhibition with the antagonist, CH223191, on IS-mediated impairment of vascular endothelial function and disruption of redox balance. The acute effects of IS on endothelium-dependent relaxation were assessed in aortic rings from Sprague Dawley rats exposed to the following conditions: (1) control; (2) IS (300 μM); (3) IS + CH223191 (1 μM); (4) IS + CH223191 (10 μM). Thereafter, tissues were assessed for changes in expression of redox markers. IS reduced the maximum level of endothelium-dependent relaxation (Rmax) by 42% ( < 0.001) compared to control, this was restored in the presence of increasing concentrations of CH223191 ( < 0.05). Rings exposed to IS increased expression of CYP1A1, nitro-tyrosine, NADPH oxidase 4 (NOX4), superoxide, and reduced eNOS expression ( < 0.05). CH223191 (10 μM) restored expression of these markers back to control levels ( < 0.05). These findings demonstrate the adverse impact of IS-mediated AhR activation on the vascular endothelium, where oxidative stress may play a critical role in inducing endothelial dysfunction in the vasculature of the heart and kidneys. AhR inhibition could provide an exciting novel therapy for CVD in the CKD setting.
尿毒症毒素吲哚硫酸酯（IS）在慢性肾脏病（CKD）中升高，已知其可导致进行性心血管疾病。IS 通过激活 CYP1A1 途径激活芳香烃受体（AhR），介导氧化应激和内皮功能障碍。本研究通过拮抗剂 CH223191 抑制 AhR，研究 IS 对血管内皮功能障碍和氧化还原平衡破坏的影响。在暴露于以下条件的 Sprague Dawley 大鼠主动脉环中评估 IS 对内皮依赖性松弛的急性影响：（1）对照；（2）IS（300μM）；（3）IS+CH223191（1μM）；（4）IS+CH223191（10μM）。然后，评估组织中氧化还原标志物的变化。与对照相比，IS 使内皮依赖性松弛的最大水平（Rmax）降低了 42%（<0.001），而随着 CH223191 浓度的增加（<0.05），这种降低得到了恢复。暴露于 IS 的环增加了 CYP1A1、硝基酪氨酸、NADPH 氧化酶 4（NOX4）、超氧化物和减少的 eNOS 表达（<0.05）。CH223191（10μM）将这些标志物的表达恢复到对照水平（<0.05）。这些发现表明，IS 介导的 AhR 激活对血管内皮具有不利影响，其中氧化应激可能在诱导心脏和肾脏血管内皮功能障碍中起关键作用。AhR 抑制可能为 CKD 中的 CVD 提供一种令人兴奋的新型治疗方法。
