Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo 142-8501, Japan.
Int J Mol Sci. 2019 Jan 15;20(2):338. doi: 10.3390/ijms20020338.
Gut microbiota are emerging as potential contributors to the regulation of host homeostasis. Dysbiosis of the gut microbiota associated with increased intestinal permeability facilitates the passage of endotoxins and other microbial products, including indoxyl sulfate in the circulation. Although an emerging body of evidence has suggested that indoxyl sulfate is a key substance for the development of chronic kidney disease, few studies have investigated the direct association of indoxyl sulfate with vascular function. We hypothesized that indoxyl sulfate adversely affects vascular function. Aortas isolated from male Wistar rat were examined in the presence or absence of indoxyl sulfate to assess the vascular function, including vasorelaxation and vasocontraction. Indoxyl sulfate (vs. vehicle) (1) decreased vasorelaxation induced by acetylcholine (ACh) but not by sodium nitroprusside; (2) had no significant alterations of noradrenaline-induced vasocontraction in the absence and presence of endothelium; (3) decreased adenylyl cyclase activator (forskolin)-induced vasorelaxation, while such a difference was eliminated by endothelial denudation; and (4) decreased vasorelaxations induced by calcium ionophore (A23187) and transient receptor potential vanilloid 4 agonist (GSK1016790A). The indoxyl sulfate-induced decrease in the vasorelaxations induced by ACh and A23187 increased by cell-permeant superoxide dismutase or by organic anion transporter inhibitor. However, apocynin, an inhibitor of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, had no effects on vasorelaxations induced by ACh, A23187, forskolin, and GSK1016790A in the presence of indoxyl sulfate. These results suggest that indoxyl sulfate directly affects the vascular function, particularly, endothelium-dependent vasorelaxation, and this effect may be attributable to increased oxidative stress after cell transportion via organic anion transporter, and such increased oxidative stress may not be attributable to activation of NADPH oxidase activation.
肠道微生物群被认为是宿主内稳态调节的潜在贡献者。与肠道通透性增加相关的肠道微生物群失调促进内毒素和其他微生物产物（包括循环中的吲哚硫酸）的通过。尽管越来越多的证据表明吲哚硫酸是慢性肾脏病发展的关键物质，但很少有研究调查吲哚硫酸与血管功能的直接关联。我们假设吲哚硫酸会对血管功能产生不利影响。在存在或不存在吲哚硫酸的情况下，检查雄性 Wistar 大鼠的主动脉，以评估血管功能，包括血管舒张和血管收缩。吲哚硫酸（与载体相比）（1）降低乙酰胆碱（ACh）诱导的血管舒张，但不降低硝普钠诱导的血管舒张；（2）在不存在和存在内皮的情况下，对去甲肾上腺素诱导的血管收缩没有显著改变；（3）降低腺苷酸环化酶激活剂（forskolin）诱导的血管舒张，而这种差异在外皮剥脱后消除；（4）降低钙离子载体（A23187）和瞬时受体电位香草醛 4 激动剂（GSK1016790A）诱导的血管舒张。吲哚硫酸诱导的 ACh 和 A23187 诱导的血管舒张减少，可以通过细胞通透性超氧化物歧化酶或有机阴离子转运体抑制剂增加。然而，烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶抑制剂 apocynin 对吲哚硫酸存在时 ACh、A23187、forskolin 和 GSK1016790A 诱导的血管舒张没有影响。这些结果表明，吲哚硫酸直接影响血管功能，特别是内皮依赖性血管舒张，这种作用可能归因于通过有机阴离子转运体细胞转运后氧化应激的增加，而这种增加的氧化应激可能不是归因于 NADPH 氧化酶的激活。
