title: Amelioration of uremic toxin indoxyl sulfate-induced endothelial cell dysfunction by Klotho protein.
abstract: 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.
authors.affiliation: Institute of Nephrology of Chongqing and Department of Nephrology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Yang
authors.forename: Ling
authors.initials: L
authors.lastname: Nie
authors.forename: Yunjian
authors.initials: Y
authors.lastname: Huang
authors.forename: Jingbo
authors.initials: J
authors.lastname: Zhang
authors.forename: Tangli
authors.initials: T
authors.lastname: Xiao
authors.forename: Xu
authors.initials: X
authors.lastname: Guan
authors.forename: Jinghong
authors.initials: J
authors.lastname: Zhao
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D005434:Flow Cytometry; D005966:Glucuronidase / Q000494:pharmacology*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D015151:Immunoblotting; D007200:Indican / Q000037:antagonists & inhibitors / Q000633:toxicity*; D000090265:Klotho Proteins; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D051436:Renal Insufficiency, Chronic / Q000378:metabolism* / Q000473:pathology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D018932:Chemokine CCL2; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D048051:p38 Mitogen-Activated Protein Kinases; D005966:Glucuronidase; D000090265:Klotho Proteins; D007200:Indican