Institute of Nephrology of Chongqing and Department of Nephrology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
Toxicol Lett. 2012 Nov 30;215(2):77-83. doi: 10.1016/j.toxlet.2012.10.004. Epub 2012 Oct 17.
Indoxyl sulfate (IS), a common kind of uremic toxin, is considered as a risk factor for aggravating endothelial function in CKD patients due to its oxidative activity. The anti-aging protein Klotho, which is produced by the kidneys and down-regulated in uremic conditions, has the ability to resist oxidative stress. Here, we carried out an in vitro study to investigate the deleterious effects of IS on endothelial cells and the protective role of Klotho protein. The cultured human umbilical vein endothelial cells (HUVECs) were incubated with IS in the presence or absence of Klotho protein. The release of reactive oxygen species (ROS) and the expression of monocyte chemoattractant protein-1 (MCP-1) were enhanced while the cell viability and production of nitric oxide (NO) were inhibited by IS in a concentration-dependent manner. Meanwhile, the phosphorylation of p38MAPK and the nuclear translocation of NF-κB were increased in HUVECs treated with IS. Pretreatment with Klotho protein resulted in remarkable increase of cell viability and decrease of ROS production in IS-treated HUVECs. Like ROS scavenger, N-acetyl-l-cysteine (NAC), Klotho protein could inhibit the IS-induced activations of p38MAPK and NF-κB. Moreover, Klotho protein could also attenuate IS-induced reduction of NO production and up-regulation of MCP-1 expression. These results suggest that IS can damage the functions of endothelial cells. Klotho protein has the ability to ameliorate the IS-induced endothelial dysfunction, which may be partly through inhibiting the ROS/p38MAPK and downstream NF-κB signaling pathways.
硫酸吲哚酚（IS）是一种常见的尿毒症毒素，由于其氧化活性，被认为是加重 CKD 患者内皮功能的危险因素。Klotho 蛋白是一种由肾脏产生的、在尿毒症条件下下调的抗衰老蛋白，具有抵抗氧化应激的能力。在这里，我们进行了一项体外研究，以探讨 IS 对内皮细胞的有害作用以及 Klotho 蛋白的保护作用。将培养的人脐静脉内皮细胞（HUVEC）与 IS 孵育，同时存在或不存在 Klotho 蛋白。IS 以浓度依赖性方式增强活性氧（ROS）的释放和单核细胞趋化蛋白-1（MCP-1）的表达，同时抑制细胞活力和一氧化氮（NO）的产生。同时，IS 处理的 HUVEC 中 p38MAPK 的磷酸化和 NF-κB 的核转位增加。Klotho 蛋白预处理可显著增加 IS 处理的 HUVEC 中的细胞活力并减少 ROS 的产生。与 ROS 清除剂 N-乙酰-L-半胱氨酸（NAC）一样，Klotho 蛋白可抑制 IS 诱导的 p38MAPK 和 NF-κB 的激活。此外，Klotho 蛋白还可以减轻 IS 诱导的 NO 产生减少和 MCP-1 表达上调。这些结果表明 IS 可以损害内皮细胞的功能。Klotho 蛋白具有改善 IS 诱导的内皮功能障碍的能力，这可能部分是通过抑制 ROS/p38MAPK 和下游 NF-κB 信号通路。
