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首页> 外文期刊>Toxicology and Applied Pharmacology >EX4 stabilizes and activates Nrf2 via PKC delta, contributing to the prevention of oxidative stress-induced pancreatic beta cell damage
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EX4 stabilizes and activates Nrf2 via PKC delta, contributing to the prevention of oxidative stress-induced pancreatic beta cell damage

机译：EX4通过PKC Delta稳定并激活NRF2，有助于预防氧化应激诱导的胰腺β细胞损伤

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摘要

Oxidative stress in pancreatic beta cells can inhibit insulin secretion and promote apoptotic cell death. Exendin-4 (EX4), a glucagon-like peptide-1 receptor agonist, can suppress beta cell apoptosis, improve beta cell function and protect against oxidative damage. In this study, we investigated the molecular mechanisms for antioxidative effects of EX4 in pancreatic beta cells. INS-1 cells, a rat insulinoma cell line, were pretreated with EX4 and exposed to palmitate or H2O2. Reactive oxygen species (ROS) production, and glutathione and insulin secretion were measured. The mRNA and protein expression levels of antioxidant genes were examined. The level of nuclear factor erythroid 2-related factor 2 (Nrf2), its binding to antioxidant response element (ARE), and its ubiquination in the presence of EX4 were determined. The Nrf2 signaling pathway was determined using rottlerin (protein kinase [PK]C delta inhibitor), H89 (PKA inhibitor) and LY294002 (phosphatidylinositide 3-kinase [PI3K] inhibitor). EX4 treatment decreased ROS production, recovered cellular glutathione levels and insulin secretion in the presence of oxidative stress in INS-1 cells. The expression levels of glutamate-cysteine ligase catalytic subunit and heme oxygenase-1 were increased by EX4 treatment EX4 promoted Nrf2 translocation, ARE binding activity and enhanced stabilization of Nrf2 by inhibition of ubiquitination. Knockdown of Nrf2 abolished the effect of EX4 on increased insulin secretion. Inhibition of PKC delta attenuated Nrf2 translocation and antioxidative gene expression by EX4 treatment We suggest that EX4 activates and stabilizes Nrf2 through PKC delta activation, contributing to the increase of antioxidant gene expression and consequently improving beta cell function in the presence of oxidative stress. (C) 2016 Elsevier Inc. All rights reserved.
机译：胰腺β细胞中的氧化应激可抑制胰岛素分泌并促进凋亡细胞死亡。Exendin-4（EX4）是胰高血糖素样肽-1受体激动剂，能抑制β细胞凋亡，改善β细胞功能，防止氧化损伤。在这项研究中，我们研究了EX4在胰腺β细胞中抗氧化作用的分子机制。INS-1细胞是一种大鼠胰岛素瘤细胞系，用EX4预处理并暴露于棕榈酸酯或H2O2。测定活性氧（ROS）产生、谷胱甘肽和胰岛素分泌。检测抗氧化基因的mRNA和蛋白质表达水平。测定了核因子红系2相关因子2（Nrf2）的水平、其与抗氧化反应元件（ARE）的结合以及在EX4存在下的泛素化。使用rottlerin（蛋白激酶[PK]Cδ抑制剂）、H89（PKA抑制剂）和LY294002（磷脂酰肌苷3-激酶[PI3K]抑制剂）测定Nrf2信号通路。在INS-1细胞存在氧化应激的情况下，EX4处理降低了ROS的产生，恢复了细胞谷胱甘肽水平和胰岛素分泌。EX4处理增加了谷氨酸半胱氨酸连接酶催化亚单位和血红素加氧酶-1的表达水平，EX4促进了Nrf2易位，增强了ARE结合活性，并通过抑制泛素化增强了Nrf2的稳定性。Nrf2基因的敲除消除了EX4对胰岛素分泌增加的影响。通过EX4处理，抑制PKCδ减弱了Nrf2易位和抗氧化基因表达。我们认为EX4通过PKCδ激活并稳定Nrf2，有助于增加抗氧化基因表达，从而在存在氧化应激的情况下改善β细胞功能。（C） 2016爱思唯尔公司版权所有。

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