Nrf2通过Keap1 / Nrf2 / p62反馈回路驱动髓核细胞中氧化应激诱导的自噬，以保护椎间盘免于变性。,Cell Death & Disease

当前位置： X-MOL 学术 › Cell Death Dis. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Nrf2通过Keap1 / Nrf2 / p62反馈回路驱动髓核细胞中氧化应激诱导的自噬，以保护椎间盘免于变性。
Cell Death & Disease ( IF 8.1 ) Pub Date : 2019-07-01 , DOI: 10.1038/s41419-019-1701-3
Zehan Tang ₁ , Bo Hu ₁ , Fazhi Zang ₁ , Jianxi Wang ₁ , Xingda Zhang ₁ , Huajiang Chen ₁

Affiliation

已知椎间盘（IVD）变性会随着年龄的增长而加剧，并且氧化应激与许多与年龄有关的疾病的发病机制有关。核因子（类胡萝卜素-2）样2（Nrf2）可以针对细胞中的氧化和蛋白毒性应激提供适应性保护。在这项研究中，我们评估了Nrf2是否可以防御髓核（NP）细胞中的氧化应激。此外，我们调查了不同程度IVD变性和衰老和IVD变性的小鼠模型以及H2O2诱导的氧化应激对NP细胞自噬途径的影响的NP组织样品中Nrf2的表达。通过测量自噬相关蛋白（ATG）家族成员和自噬标记p62和LC3的水平来评估自噬。我们发现在IVD变性程度增加的患者的人NP组织样本中，Nrf2的表达逐渐降低。Nrf2缺乏会导致IVD在衰老过程中退化。Nrf2敲除还加剧了IVD变性，并在诱导的IVD变性小鼠模型中降低了自噬基因的表达。通过减少Atg7的表达和Keap1-Nrf2-p62自噬途径，H2O2诱导的氧化应激的有害作用在自噬缺陷细胞中增加。综上，这些结果表明，过度的氧化应激会导致自噬的上调，而自噬是IVD变性中由Keap1-Nrf2-p62反馈回路激活的抗氧化剂反馈响应。Nrf2缺乏会导致IVD在衰老过程中退化。Nrf2敲除还加剧了IVD变性，并在诱导的IVD变性小鼠模型中降低了自噬基因的表达。通过减少Atg7的表达和Keap1-Nrf2-p62自噬途径，H2O2诱导的氧化应激的有害作用在自噬缺陷细胞中增加。综上，这些结果表明，过度的氧化应激会导致自噬的上调，而自噬是IVD变性中由Keap1-Nrf2-p62反馈回路激活的抗氧化剂反馈响应。Nrf2缺乏会导致IVD在衰老过程中退化。Nrf2敲除还加剧了IVD变性，并在诱导的IVD变性小鼠模型中降低了自噬基因的表达。通过减少Atg7的表达和Keap1-Nrf2-p62自噬途径，H2O2诱导的氧化应激的有害作用在自噬缺陷细胞中增加。综上，这些结果表明，过度的氧化应激会导致自噬的上调，而自噬是IVD变性中由Keap1-Nrf2-p62反馈回路激活的抗氧化剂反馈响应。通过减少Atg7的表达和Keap1-Nrf2-p62自噬途径，H2O2诱导的氧化应激的有害作用在自噬缺陷细胞中增加。综上，这些结果表明，过度的氧化应激会导致自噬的上调，而自噬是IVD变性中由Keap1-Nrf2-p62反馈回路激活的抗氧化剂反馈响应。通过减少Atg7的表达和Keap1-Nrf2-p62自噬途径，H2O2诱导的氧化应激的有害作用在自噬缺陷细胞中增加。综上，这些结果表明，过度的氧化应激会导致自噬的上调，而自噬是IVD变性中由Keap1-Nrf2-p62反馈回路激活的抗氧化剂反馈响应。

"点击查看英文标题和摘要"

Nrf2 drives oxidative stress-induced autophagy in nucleus pulposus cells via a Keap1/Nrf2/p62 feedback loop to protect intervertebral disc from degeneration.

Intervertebral disc (IVD) degeneration is known to aggravate with age and oxidative stress is implicated in the pathogenesis of many age-related diseases. Nuclear factor (erythroid-derived-2)-like 2 (Nrf2) can confer adaptive protection against oxidative and proteotoxic stress in cells. In this study, we assessed whether Nrf2 can protect against oxidative stress in nucleus pulposus (NP) cells. In addition, we investigated Nrf2 expression in NP tissue samples from patients with different degrees of IVD degeneration and a mouse model of aging and IVD degeneration and the influence of H2O2-induced oxidative stress on autophagic pathways in NP cells. Autophagy was assessed by measuring levels of autophagy-related protein (ATG) family members and the autophagic markers, p62 and LC3. We found that expression of Nrf2 progressively decreased in human NP tissue samples of patients with increasing degrees of IVD degeneration. Nrf2 deficiency leads to the degeneration of IVDs during aging. Nrf2 knockout also aggravates IVD degeneration and reduces autophagic gene expression in an induced mouse model of IVD degeneration. The detrimental effects of H2O2-induced oxidative stress were increased in autophagy-deficient cells via reduced expression of Atg7 and the Keap1-Nrf2-p62 autophagy pathway. Taken together, these results suggest that excessive oxidative stress causes the upregulation of autophagy, and autophagy acts as an antioxidant feedback response activated by a Keap1-Nrf2-p62 feedback loop in IVD degeneration.

更新日期：2019-07-01

点击分享查看原文

点击收藏

公开下载

阅读更多本刊新发论文本刊介绍/投稿指南