1] Aix Marseille Université, INSERM UMR_S 1076, Marseille, France [2] Centre de Néphrologie et Transplantation Rénale, Hôpital de la Conception, Assistance Publique-Hôpitaux de Marseille, Marseille, France.
Kidney Int. 2013 Oct;84(4):733-44. doi: 10.1038/ki.2013.133. Epub 2013 May 1.
In chronic kidney disease (CKD), uremic solutes accumulate in blood and tissues. These compounds probably contribute to the marked increase in cardiovascular risk during the progression of CKD. The uremic solutes indoxyl sulfate and indole-3-acetic acid (IAA) are particularly deleterious for endothelial cells. Here we performed microarray and comparative PCR analyses to identify genes in endothelial cells targeted by these two uremic solutes. We found an increase in endothelial expression of tissue factor in response to indoxyl sulfate and IAA and upregulation of eight genes regulated by the transcription factor aryl hydrocarbon receptor (AHR). The suggestion by microarray analysis of an involvement of AHR in tissue factor production was confirmed by siRNA inhibition and the indirect AHR inhibitor geldanamycin. These observations were extended to peripheral blood mononuclear cells. Tissue factor expression and activity were also increased by AHR agonist dioxin. Finally, we measured circulating tissue factor concentration and activity in healthy control subjects and in patients with CKD (stages 3-5d), and found that each was elevated in patients with CKD. Circulating tissue factor levels were positively correlated with plasma indoxyl sulfate and IAA. Thus, indolic uremic solutes increase tissue factor production in endothelial and peripheral blood mononuclear cells by AHR activation, evoking a 'dioxin-like' effect. This newly described mechanism of uremic solute toxicity may help understand the high cardiovascular risk of CKD patients.
在慢性肾脏病（CKD）中，尿毒症溶质在血液和组织中积累。这些化合物可能导致 CKD 进展过程中心血管风险显著增加。尿毒症溶质硫酸吲哚酚和吲哚-3-乙酸（IAA）对内皮细胞尤其有害。在这里，我们进行了微阵列和比较 PCR 分析，以确定这两种尿毒症溶质靶向的内皮细胞中的基因。我们发现，内皮细胞中组织因子的表达在硫酸吲哚酚和 IAA 的作用下增加，转录因子芳烃受体（AHR）调节的八个基因上调。微阵列分析表明 AHR 参与组织因子的产生，这一建议得到了 siRNA 抑制和间接 AHR 抑制剂格尔德霉素的证实。这些观察结果扩展到外周血单核细胞。组织因子的表达和活性也被 AHR 激动剂二恶英增加。最后，我们测量了健康对照组和 CKD 患者（3-5d 期）的循环组织因子浓度和活性，发现 CKD 患者的每种都升高。循环组织因子水平与血浆硫酸吲哚酚和 IAA 呈正相关。因此，吲哚尿毒症溶质通过 AHR 激活增加内皮细胞和外周血单核细胞中的组织因子产生，引发“二恶英样”效应。这种新描述的尿毒症溶质毒性机制可能有助于理解 CKD 患者的高心血管风险。
