Amelioration of uremic toxin indoxyl sulfate-induced endothelial cell dysfunction by Klotho protein
Amelioration of uremic toxin indoxyl sulfate-induced endothelial cell dysfunction by Klotho protein
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Klotho 蛋白改善尿毒症毒素硫酸吲哚酚诱导的内皮细胞功能障碍
DOI：
10.1016/j.toxlet.2012.10.004
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发表时间：
2012-11-30
影响因子：
3.5
通讯作者：
Zhao, Jinghong
中科院分区：
文献类型：
--
作者：
Yang, Ke;Nie, Ling;Zhao, Jinghong
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。抗衰老蛋白 Klotho 由肾脏产生，在尿毒症情况下下调，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，以研究 IS 对内皮细胞的有害影响以及 Klotho 蛋白的保护作用。在存在或不存在 Klotho 蛋白的情况下，将培养的人脐静脉内皮细胞 (HUVEC) 与 IS 一起孵育。 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，在 IS 处理的 HUVEC 中，p38MAPK 的磷酸化和 NF-κ B 的核转位增加。在 IS 处理的 HUVEC 中，用 Klotho 蛋白进行预处理可显着提高细胞活力并减少 ROS 产生。与 ROS 清除剂 N-乙酰-L-半胱氨酸 (NAC) 一样，Klotho 蛋白可以抑制 IS 诱导的 p38MAPK 和 NF-kappa B 激活。此外，Klotho 蛋白还可以减弱 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，部分原因可能是通过抑制 ROS/ p38MAPK 和下游 NF-kappa B 信号通路。 (C) 2012 Elsevier Ireland Ltd. 保留所有权利。
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-kappa B 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-kappa B. 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-kappa B signaling pathways. (C) 2012 Elsevier Ireland Ltd. All rights reserved.