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Enhancer of zeste homolog 2 modulates oxidative stress‐mediated pyroptosis in vitro and in a mouse kidney ischemia‐reperfusion injury model
Author(s) -
Liu Hao,
Chen Zhiyuan,
Weng Xiaodong,
Chen Hui,
Du Yang,
Diao Changhui,
Liu Xiuheng,
Wang Lei
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201901816r
Subject(s) - pyroptosis , nox4 , oxidative stress , gene knockdown , chemistry , reactive oxygen species , ezh2 , microbiology and biotechnology , renal ischemia , nadph oxidase , biology , cancer research , reperfusion injury , programmed cell death , apoptosis , histone , ischemia , biochemistry , medicine , gene
Enhancer of zeste homolog 2 (EZH2), a well‐known methyltransferase, mediates histone H3 lysine 27 trimethylation (H3K27me3) and plays a crucial role in several kidney disease models. However, its role in renal ischemia/reperfusion (I/R) injury still remains unclear. In this study, we found that EZH2 was positively related to renal I/R injury and inhibition of EZH2 with DZNeP alleviated I/R injury and blocked the activation of oxidative stress and pyroptosis in vivo. Similarly, inhibition of EZH2 with either DZNeP or si‐RNA also exerted an inhibitory effect on hypoxia/reoxygenation (H/R)‐induced oxidative stress and pyroptosis in vitro. Moreover, further study revealed that ablation of reactive oxygen species (ROS) with N‐acetyl‐cysteine (NAC) suppressed pyroptosis in human renal proximal tubular epithelial cell line cells exposed to H/R stimulation. Furthermore, Nox4, which was positively related to the generation of ROS, was upregulated during H/R process, while it could be reversed by EZH2 inhibition. Consistently, Nox4‐mediated ROS generation was attenuated upon inhibition of EZH2 with DZNeP or si‐RNA. Additionally, the transcriptional activity of Nox4 was enhanced by the activation of ALK5/Smad2/3 signaling pathway, which was abolished by ALK5 knockdown in vitro. Finally, EZH2 inhibition blocked H/R and I/R‐activated ALK5/Smad2/3 pathway and also resulted in an obvious decrease in the transcriptional activity and protein expression levels of Nox4. In conclusion, our results proved that EZH2 inhibition alleviated renal pyroptosis by blocking Nox4‐dependent ROS generation through ALK5/Smad2/3 signaling pathway, indicating that EZH2 could be a potential therapeutic target for renal I/R injury.