Persistent activation of Nrf2 in a p62-dependent non-canonical manner aggravates lead-induced kidney injury by promoting apoptosis and inhibiting autophagy

• Published in: Journal of advanced research 2023-04, Vol.46, p.87-100
• Main Authors: Lian, Cai-Yu, Chu, Bing-Xin, Xia, Wei-Hao, Wang, Zhen-Yong, Fan, Rui-Feng, Wang, Lin
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Autophagy; Humans; Kelch-Like ECH-Associated Protein 1 - metabolism; Kidney; Kidney injury; Lead; Lead - metabolism; Lead - toxicity; NF-E2-Related Factor 2 - metabolism; NF-E2-Related Factor 2 - pharmacology; Nrf2; Original; Rats
• ISSN: 2090-1232; 2090-1224
• DOI: 10.1016/j.jare.2022.04.016

Graphical diagram illustrating the function and mechanism of Nrf2 in Pb-induced kidney injury. [Display omitted] •Lead (Pb)-induced persistent Nrf2 activation contributes to kidney injury.•Persistent Nrf2 activation promotes apoptosis and autophagic blockage.•Nrf2 is persistently activated in a p62-dependent non-canonical manner. 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. 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. 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. 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.