TRIM16通过下调Keap1增强Nrf2 / ARE抗氧化信号，从而保护OGD / R诱导的海马神经元氧化应激。,Experimental Cell Research

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TRIM16通过下调Keap1增强Nrf2 / ARE抗氧化信号，从而保护OGD / R诱导的海马神经元氧化应激。
Experimental Cell Research ( IF 3.3 ) Pub Date : 2020-04-03 , DOI: 10.1016/j.yexcr.2020.111988
Xiaoyan Ren ₁ , Jiangang Yu ₁ , Lili Guo ₁ , Hong Ma ₁

Affiliation

三方基序16（TRIM16）已作为一种新型的氧化应激反应蛋白出现，该蛋白通过增强细胞抗氧化剂系统赋予细胞保护作用。然而，尚不清楚TRIM16是否参与调节脑缺血/再灌注损伤期间的氧化应激。在本研究中，我们旨在探索TRIM16在调节氧-葡萄糖剥夺/复氧（OGD / R）诱导的神经元氧化应激中的潜在功能和分子机制。在这里，我们发现OGD / R暴露导致神经元中TRIM16表达的明显诱导。siRNA介导的基因敲低对TRIM16的消耗显着上调了神经元对OGD / R诱导的凋亡和活性氧（ROS）生成的敏感性。值得注意的是 TRIM16表达的上调显着减轻了OGD / R诱导的神经元凋亡和ROS生成。此外，TRIM16的过表达显着增加了核因子类红细胞2相关因子2（Nrf2）的表达，并增强了Nrf2 /抗氧化反应元件（ARE）的激活，这些表达与海藻样ECH相关蛋白1（Keap1）的表达下调有关。Keap1的恢复大大逆转了TRIM16介导的对Nrf2 / ARE激活的促进作用。此外，敲除Nrf2还显着消除了OGD / R暴露神经元中赋予TRIM16的神经保护作用。两者合计，我们的研究结果表明，TRIM16的诱导通过下调Keap1增强Nrf2 / ARE抗氧化剂信号传导，从而在OGD / R暴露的神经元中赋予细胞保护作用。

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TRIM16 protects from OGD/R-induced oxidative stress in cultured hippocampal neurons by enhancing Nrf2/ARE antioxidant signaling via downregulation of Keap1.

Tripartite motif 16 (TRIM16) has emerged as a novel oxidative stress-responsive protein that confers cytoprotective effects by reinforcing the cellular antioxidant system. However, whether TRIM16 is involved in regulating oxidative stress during cerebral ischemia/reperfusion injury remains unclear. In the present study, we aimed to explore the potential function and molecular mechanism of TRIM16 in regulating oxidative stress in neurons induced by oxygen-glucose deprivation/reoxygenation (OGD/R) in vitro. Here, we found that OGD/R exposure resulted in a significant induction of TRIM16 expression in neurons. Depletion of TRIM16 by siRNA-mediated gene knockdown markedly upregulated the sensitivity of neurons to OGD/R-induced apoptosis and reactive oxygen species (ROS) generation. Notably, upregulation of TRIM16 expression significantly alleviated OGD/R-induced apoptosis and ROS generation in neurons. Moreover, TRIM16 overexpression markedly increased nuclear factor erythroid 2-related factor 2 (Nrf2) expression and enhanced Nrf2/antioxidant response element (ARE) activation associated with downregulation of kelch-like ECH-associated protein 1 (Keap1) expression. Restoration of Keap1 significantly reversed the TRIM16-mediated promotion effect on Nrf2/ARE activation. In addition, knockdown of Nrf2 also markedly abrogated the TRIM16-conferred neuroprotective effect in OGD/R-exposed neurons. Taken together, our results of our study demonstrate that induction of TRIM16 confers a cytoprotective effect in OGD/R-exposed neurons through enhancement of Nrf2/ARE antioxidant signaling via downregulation of Keap1. These findings suggest that TRIM16 may play a critical role in cerebral ischemia/reperfusion injury and serve as a promising target for neuroprotection.

更新日期：2020-04-03

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