Indoxyl Sulfate Induces Endothelial Cell Senescence by Increasing Reactive Oxygen Species Production and p53 Activity
Indoxyl Sulfate Induces Endothelial Cell Senescence by Increasing Reactive Oxygen Species Production and p53 Activity
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DOI：
10.1053/j.jrn.2011.10.027
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发表时间：
2012-01-01
影响因子：
3.2
通讯作者：
Niwa, Toshimitsu
中科院分区：
文献类型：
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作者：
Adelibieke, Yelixiati;Shimizu, Hidehisa;Niwa, Toshimitsu
背景/目的：我们已经报道了硫酸吲哚酚（IS），一种尿毒症毒素，加速近端肾小管细胞衰老。不对称二甲基精氨酸（ADMA）是一种一氧化氮合酶抑制剂，已被报道可诱导内皮细胞衰老。本研究旨在确定是否是诱导内皮细胞衰老的ADMA相比，并探讨其分子mechanism.Methods：人脐静脉内皮细胞（HUVECs）与IS（250 μ M）和/或ADMA（10 mM）孵育。这些浓度与血液透析患者的平均血清水平相当。通过测量衰老相关的β-半乳糖苷酶（SA-β-gal）活性来评价细胞衰老。用抗氧化剂N-乙酰半胱氨酸和p53抑制剂pifithrin alpha p-nitro研究活性氧和p53在诱导HUVECs衰老中的作用。此外，当IS和ADMA共孵育时，观察到SA-b-gal活性的一些额外增加。N-乙酰半胱氨酸或pifithrin alpha p-nitro预孵育显著抑制IS和ADMA诱导的HUVECs SA-b-gal活性。结论：IS和ADMA均通过增加ROS和p53活性诱导内皮细胞衰老。(C)2012年，美国国家肾脏基金会（National Kidney Foundation，Inc.）All rights reserved.
Background/Aim: We have reported that indoxyl sulfate (IS), a uremic toxin, accelerates proximal tubular cell senescence. Asymmetric dimethylarginine (ADMA), an inhibitor of nitric oxide synthase, has been reported to induce endothelial cell senescence. This study aimed to determine whether IS induces endothelial cell senescence in comparison with ADMA, and to investigate its molecular mechanism.Methods: Human umbilical vein endothelial cells (HUVECs) were incubated with IS (250 mu M) and/or ADMA (10 mM). These concentrations were comparable with their mean serum levels in hemodialysis patients. Cell senescence was evaluated by measuring senescence-associated beta-galactosidase (SA-beta-gal) activity. N-acetylcysteine, an antioxidant, and pifithrin alpha p-nitro, a p53 inhibitor, were used to determine the role of reactive oxygen species (ROS) and p53 in the induction of cell senescence.Results: Both IS and ADMA significantly increased SA-b-gal activity in HUVECs. Further, some additional increase in SA-b-gal activity was observed when IS and ADMA were co-incubated. Preincubation of N-acetylcysteine or pifithrin alpha p-nitro significantly inhibited SA-b-gal activity induced by IS and ADMA in HUVECs. Thus, both IS and ADMA induced endothelial senescence through ROS and p53.Conclusion: IS induces endothelial cell senescence by increasing ROS production and p53 activity, like ADMA. (C) 2012 by the National Kidney Foundation, Inc. All rights reserved.