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Persistent activation of Nrf2 in a p62-dependent non-canonical manner aggravates lead-induced kidney injury by promoting apoptosis and inhibiting autophagy
Journal of Advanced Research ( IF 10.7 ) Pub Date : 2022-05-02 , DOI: 10.1016/j.jare.2022.04.016
Cai-Yu Lian 1 , Bing-Xin Chu 2 , Wei-Hao Xia 1 , Zhen-Yong Wang 1 , Rui-Feng Fan 1 , Lin Wang 1
Affiliation  

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.



中文翻译:

以 p62 依赖性非典型方式持续激活 Nrf2 通过促进细胞凋亡和抑制自噬加重铅诱导的肾损伤

介绍

铅 (Pb) 是一种环境毒物,会对人类和动物造成严重的健康风险,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。

目标

核因子红细胞 2 相关因子 2 (Nrf2) 是抵消氧化损伤的主要贡献者,而 Nrf2 通路的过度激活或耗竭可导致氧化还原失衡,从而引起组织损伤。本研究旨在阐明 Nrf2 在铅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 暴露可激活原代大鼠近端肾小管细胞中的 Nrf2 通路。接下来,Pb 诱导的 Nrf2 激活通过药理学调节或 siRNA 介导的体外体内敲低有效调节。值得注意的是,铅触发的细胞毒性、肾损伤和伴随的细胞凋亡通过 Nrf2 下调得到改善,证实铅诱导的持续 Nrf2 激活有助于肾毒性。此外,Nrf2 下调缓解了 Pb 触发的自噬阻滞。从机制上讲,我们发现 Pb 诱导的持续 Nrf2 激活归因于 Nrf2 泛素化减少和 Keap1 以 p62 依赖性方式的核 - 细胞质丢失。

结论

总之,这些发现突出了持续性 Nrf2 激活的阴暗面和铅诱导的持续性 Nrf2 激活、细胞凋亡和铅引发的肾毒性中的自噬阻断之间的潜在串扰。

更新日期:2022-05-02
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