常染色体显性多囊肾病
氧化应激
增强子
包装D1
活性氧
细胞生物学
调解人
生物
多囊肾病
平衡
KEAP1型
内分泌学
氧化磷酸化
肾
基因
遗传学
转录因子
生物化学
作者
Yi Lü,Yongzhan Sun,Zhiheng Liu,Yumei Lu,Xu Zhu,Bingxue Lan,Zeyun Mi,Lin Dang,Na Li,Wenlei Zhan,Lu Tan,Jingbo Pi,Hongchun Xiong,Lirong Zhang,Yupeng Chen
出处
期刊:Science Translational Medicine
[American Association for the Advancement of Science (AAAS)]
日期:2020-07-29
卷期号:12 (554)
被引量:66
标识
DOI:10.1126/scitranslmed.aba3613
摘要
Oxidative stress is emerging as a crucial contributor to the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD), but the molecular mechanisms underlying the disturbed redox homeostasis in cystic cells remain elusive. Here, we identified the impaired activity of the NRF2 (nuclear factor erythroid 2-related factor 2) antioxidant pathway as a driver of oxidative damage and ADPKD progression. Using a quantitative proteomic approach, together with biochemical analyses, we found that increased degradation of NRF2 protein suppressed the NRF2 antioxidant pathway in ADPKD mouse kidneys. In a cohort of patients with ADPKD, reactive oxygen species (ROS) frequently accumulated, and their production correlated negatively with NRF2 abundance and positively with disease severity. In an orthologous ADPKD mouse model, genetic deletion of Nrf2 further increased ROS generation and promoted cyst growth, whereas pharmacological induction of NRF2 reduced ROS production and slowed cystogenesis and disease progression. Mechanistically, pharmacological induction of NRF2 remodeled enhancer landscapes and activated NRF2-bound enhancer-associated genes in ADPKD cells. The activation domain of NRF2 formed phase-separated condensates with MEDIATOR complex subunit MED16 in vitro, and optimal Mediator recruitment to genomic loci depended on NRF2 in vivo. Together, these findings indicate that NRF2 remodels enhancer landscapes and activates its target genes through a phase separation mechanism and that activation of NRF2 represents a promising strategy for restoring redox homeostasis and combatting ADPKD.
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