Advanced glycation end products enhance reactive oxygen and nitrogen species generation in neutrophils in vitro
Advanced glycation end products enhance reactive oxygen and nitrogen species generation in neutrophils in vitro
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DOI：
10.1007/s11010-011-1114-9
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发表时间：
2012-02-01
影响因子：
4.3
通讯作者：
Tripathi, Ashok K.
中科院分区：
文献类型：
--
作者：
Bansal, Savita;Siddarth, Manushi;Tripathi, Ashok K.
糖尿病氧化应激（OS）升高是导致糖尿病病理的主要因素之一。然而，引起糖尿病OS的介质和机制尚不完全清楚，可能是高血糖后晚期糖基化终产物（AGEs）的积累刺激循环多形核中性粒细胞（PMN）产生活性氧（ROS）。在本报告中，我们旨在研究AGE对PMN中活性氧和氮的产生以及随后的OS的影响。AGE-HSA对PMN产生的ROS和活性氮中间体（RNI）产生具有剂量和时间依赖性的增强作用。研究发现，ROS和RNI生成的增加分别是通过NADPH氧化酶和诱导型一氧化氮合酶（iNOS）的上调介导的，这一点从age处理的中性粒细胞在二苯乙烯（一种抑制这两种酶的黄蛋白抑制剂）存在下无法产生ROS和RNI这一事实中得到了证明。当细胞与抗rage抗体孵育时，进一步增加的ROS和RNI的产生停止，这表明AGE-RAGE相互作用的参与。此外，AGE暴露的PMN中丙二醛（MDA）和蛋白羰基形成的增加表明AGE诱导了OS。本研究提供的证据表明，AGEs可能通过增加pmn介导的ROS和RNI的生成，在诱导氧化应激中发挥关键作用，这可能是AGEs诱导的糖尿病病理发展的部分原因。
Increased oxidative stress (OS) in diabetes mellitus is one of the major factors leading to diabetic pathology. However, the mediators and mechanism that provoke OS in diabetes is not fully understood, and it is possible that accumulation of advanced glycation end products (AGEs) formed secondary to hyperglycemic conditions may incite circulating polymorphonuclear neutrophils (PMN) to generate reactive oxygen species (ROS). In this report, we aim to investigate the effect of AGE on reactive oxygen and nitrogen species generation and subsequent OS in PMN. AGE-HSA exert dose- and time-dependent enhancement of ROS and reactive nitrogen intermediates (RNI) generation by PMN. Increased ROS and RNI generation were found to be mediated through the upregulation of NADPH oxidase and inducible nitric oxide synthase (iNOS), respectively, as evident from the fact that AGE-treated neutrophils failed to generate ROS and RNI in presence of diphenyleneiodonium, a flavoprotein inhibitor for both enzymes. Further increased generation of ROS and RNI ceased when the cells were incubated with anti-RAGE antibody suggesting the involvement of AGE-RAGE interaction. Also increased malondialdehyde (MDA) and protein carbonyl formation in AGE-exposed PMN suggest induction of OS by AGE. This study provides evidence that AGEs may play a key role in the induction of oxidative stress through the augmentation of PMN-mediated ROS and RNI generation and this may be in part responsible for development of AGE-induced diabetic pathology.