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首页> 外文期刊>Molecular medicine reports >Activation of the Notch-Nox4-reactive oxygen species signaling pathway induces cell death in high glucose-treated human retinal endothelial cells
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Activation of the Notch-Nox4-reactive oxygen species signaling pathway induces cell death in high glucose-treated human retinal endothelial cells

机译：Notch-Nox4-反应性氧物种信号传导途径的激活诱导细胞死亡在高葡萄糖处理的人视网膜内皮细胞中

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Diabetic retinopathy (DR) occurs in almost all patients with diabetes and remains as one of the major causes of vision loss worldwide. Nevertheless, the molecular mechanisms underlying the pathogenesis of DR remain elusive. The present study aimed to investigate the role and association of Notch signaling and NADPH oxidase 4 (Nox4)-mediated oxidative stress in high glucose (HG)-treated retinal cells. Human retinal endothelial cells were cultured for various durations in RPMI-1640 medium containing 30 mM glucose (HG) or 30 mM mannitol (MN) as an osmotic control; apoptotic cell death and reactive oxygen species (ROS) levels were assessed, respectively. Alterations in the expression profiles of Nox and Notch proteins were evaluated using reverse transcription-quantitative polymerase chain reaction and western blot analysis. Knockdown of Nox4 and recombination signal-binding protein J (RBPj) was generated by transfection with specific small interfering (siRNA). Persistent activation of Notch signaling was induced via the overexpression of Notch intracellular domain (NICD). In the present study, time-dependent increases in ROS production and cell death were detected in HG-treated cells. Depletion of ROS by diphenyleneiodonium decreased HG-induced cell death, and suppressed increases in caspase 3 activity and B-cell lymphoma 2-associated X protein levels. In HG-treated cells, Nox4 expression was upregulated at the mRNA and protein levels, and inhibition of Nox4 by GKT137831 or knockdown of expression by siRNA Nox4 significantly reduced ROS levels and cell death. In the presence of HG, Notch1 expression levels were elevated, and increased NICD abundance was detected in whole cell lysates and nuclear fractions. Additionally, HG-induced cell death was decreased by treatment with -secretase inhibitor (GSI), but increased via the overexpression of NICD. The application of GSI or knockdown of RBPj by siRNA RBPj prevented increases in Nox4 expression within HG-treated cells. The findings of the present study demonstrated that Nox4-mediated ROS serves an important role in HG-induced retinal cell damage, in which the activation of Notch signaling may be responsible for Nox4 upregulation. Therefore, inhibition of Notch signaling or Nox4 expression may be considered as potential therapeutic targets in patients with DR.
机译：糖尿病视网膜病变（DR）发生在几乎所有糖尿病患者中，并且仍然是全球视力丧失的主要原因之一。然而，博士的发病机制下面的分子机制仍然难以捉摸。本研究旨在研究Notch信号传导和NADPH氧化酶4（NOX4）介导的氧化应激在高葡萄糖（HG）的视网膜细胞中的作用和关联。将人视网膜内皮细胞培养以含有30mM葡萄糖（Hg）或30mM甘露醇（Mn）的RPMI-1640培养基中的各种持续时间作为渗透控制;分别评估凋亡细胞死亡和反应性氧物质（ROS）水平。使用逆转录定量聚合酶链反应和Western印迹分析评估NOx和Notch蛋白表达蛋白表达谱的改变。通过用特定的小干扰（siRNA）转染产生NOx4和重组信号结合蛋白J（RBPJ）的敲低。通过凹口细胞内结构域（NICD）的过表达诱导凹口信令的持续激活。在本研究中，在HG处理细胞中检测到ROS生产和细胞死亡中的时间依赖性增加。二苯基碘碘鎓的ROS耗尽降低了HG诱导的细胞死亡，并且抑制了Caspase 3活性和B细胞淋巴瘤2相关X蛋白水平的增加。在HG处理的细胞中，在mRNA和蛋白质水平上上调NOx4表达，并通过GKT137831抑制NOx4或SiRNA NOX4的表达敲低显着降低了ROS水平和细胞死亡。在Hg存在下，升高Notch1表达水平，并在全细胞裂解物和核级分中检测到增加的NICD丰度。另外，通过用-SecretAse抑制剂（GSI）处理，降低HG诱导的细胞死亡，但通过NICD的过度表达增加。 SiRNA RBPJ通过SiRNA RBPJ的GSI或敲低的应用阻止了HG处理细胞内NOx4表达的增加。本研究的发现证明NOX4介导的ROS在HG诱导的视网膜细胞损伤中用于缺口信号传导的激活可能对NOx4上调负责。因此，抑制缺口信号传导或NOX4表达可以被认为是博士患者的潜在治疗靶标。

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