以 p62 依赖性非经典方式持续激活 Nrf2 通过促进细胞凋亡和抑制自噬加重铅诱导的肾损伤。
Persistent activation of Nrf2 in a p62-dependent non-canonical manner aggravates lead-induced kidney injury by promoting apoptosis and inhibiting autophagy.
机构信息
College of Animal Science and Veterinary Medicine, Shandong Agricultural University, 61 Daizong Street, Tai'an City, Shandong Province 271018, China; Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, 61 Daizong Street, Tai'an City, Shandong Province 271018, China; Shandong Provincial Engineering Technology Research Center of Animal Disease Control and Prevention, Shandong Agricultural University, 61 Daizong Street, Tai'an City, Shandong Province 271018, China.
College of Animal Science and Veterinary Medicine, Shandong Agricultural University, 61 Daizong Street, Tai'an City, Shandong Province 271018, China; Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, 61 Daizong Street, Tai'an City, Shandong Province 271018, China; Shandong Provincial Engineering Technology Research Center of Animal Disease Control and Prevention, Shandong Agricultural University, 61 Daizong Street, Tai'an City, Shandong Province 271018, China; College of Veterinary Medicine, China Agricultural University, Beijing 100193, China.
出版信息
J Adv Res. 2023 Apr;46:87-100. doi: 10.1016/j.jare.2022.04.016. Epub 2022 May 2.
INTRODUCTION
Lead (Pb) is an environmental toxicant that poses severe health risks to humans and animals, especially renal disorders. Pb-induced nephrotoxicity has been attributed to oxidative stress, in which apoptosis and autophagy are core events.
OBJECTIVES
Nuclear factor erythroid 2-related factor 2 (Nrf2) acts as a major contributor to counteract oxidative damage, while hyperactivation or depletion of Nrf2 pathway can cause the redox imbalance to induce tissue injury. This study was performed to clarify the function and mechanism of Nrf2 in Pb-triggered kidney injury.
METHODS AND RESULTS
First, data showed that Pb exposure activates Nrf2 pathway in primary rat proximal tubular cells. Next, Pb-induced Nrf2 activation was effectively regulated by pharmacological modulation or siRNA-mediated knockdown in vitro and in vivo assays. Notably, Pb-triggered cytotoxicity, renal injury and concomitant apoptosis were improved by Nrf2 downregulation, confirming that Pb-induced persistent Nrf2 activation contributes to nephrotoxicity. Additionally, Pb-triggered autophagy blockage was relieved by Nrf2 downregulation. Mechanistically, we found that Pb-induced persistent Nrf2 activation is attributed to reduced Nrf2 ubiquitination and nuclear-cytoplasmic loss of Keap1 in a p62-dependent manner.
CONCLUSIONS
In conclusion, these findings highlight the dark side of persistent Nrf2 activation and potential crosstalk among Pb-induced persistent Nrf2 activation, apoptosis and autophagy blockage in Pb-triggered nephrotoxicity.
简介
铅（Pb）是一种环境毒物，对人类和动物的健康构成严重威胁，尤其是肾脏疾病。铅诱导的肾毒性归因于氧化应激，其中细胞凋亡和自噬是核心事件。
目的
核因子红细胞 2 相关因子 2（Nrf2）作为对抗氧化损伤的主要贡献者，而 Nrf2 途径的过度激活或耗竭会导致氧化还原失衡，从而引起组织损伤。本研究旨在阐明 Nrf2 在 Pb 引发的肾损伤中的功能和机制。
方法和结果
首先，数据显示 Pb 暴露在原代大鼠近端肾小管细胞中激活了 Nrf2 途径。接下来，在体外和体内实验中，通过药理学调节或 siRNA 介导的敲低有效地调节了 Pb 诱导的 Nrf2 激活。值得注意的是，通过下调 Nrf2，Pb 诱导的细胞毒性、肾损伤和伴随的细胞凋亡得到改善，证实了 Pb 诱导的持续 Nrf2 激活导致肾毒性。此外，通过下调 Nrf2，Pb 诱导的自噬阻断得到缓解。从机制上讲，我们发现 Pb 诱导的持续 Nrf2 激活归因于 p62 依赖性的 Nrf2 泛素化减少和 Keap1 的核质丢失。
结论
总之，这些发现强调了持续 Nrf2 激活的阴暗面，以及 Pb 诱导的持续 Nrf2 激活、凋亡和自噬阻断之间在 Pb 引发的肾毒性中的潜在相互作用。
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