Activation of NRF2 ameliorates oxidative stress and cystogenesis in autosomal dominant polycystic kidney disease
Activation of NRF2 ameliorates oxidative stress and cystogenesis in autosomal dominant polycystic kidney disease
复制标题
NRF2 的激活可改善常染色体显性多囊肾病的氧化应激和囊肿发生
DOI：
10.1126/scitranslmed.aba3613
复制
发表时间：
2020-07-29
影响因子：
17.1
通讯作者：
Chen, Yupeng
中科院分区：
文献类型：
--
作者：
Lu, Yi;Sun, Yongzhan;Chen, Yupeng
氧化应激正逐渐成为常染色体显性多囊肾病（ADPKD）发病机制的关键因素，但囊性细胞中氧化还原稳态失衡的分子机制仍不清楚。在此，我们确定核因子E2相关因子2（NRF2）抗氧化通路活性受损是氧化损伤和ADPKD进展的驱动因素。通过定量蛋白质组学方法以及生化分析，我们发现NRF2蛋白降解增加抑制了ADPKD小鼠肾脏中的NRF2抗氧化通路。在一组ADPKD患者中，活性氧（ROS）经常积累，其产生与NRF2丰度呈负相关，与疾病严重程度呈正相关。在同源ADPKD小鼠模型中，Nrf2基因缺失进一步增加了ROS的产生并促进了囊肿生长，而NRF2的药理诱导减少了ROS的产生，减缓了囊肿形成和疾病进展。从机制上讲，NRF2的药理诱导重塑了增强子景观并激活了ADPKD细胞中与NRF2结合的增强子相关基因。NRF2的激活域在体外与中介体复合物亚基MED16形成相分离凝聚物，并且在体内中介体向基因组位点的最佳募集依赖于NRF2。总之，这些发现表明NRF2通过相分离机制重塑增强子景观并激活其靶基因，并且NRF2的激活是恢复氧化还原稳态和对抗ADPKD的一种有前景的策略。
Pharmacological induction of NRF2 restores redox homeostasis and slows cystogenesis in mouse models of polycystic kidney disease. Antioxidants dominate ADPKD Autosomal dominant polycystic kidney disease (ADPKD) is a relatively common genetic disorder whose pathogenesis is only partially understood. By studying both human patients and mouse models, Lu et al. identified inactivating mutations of the antioxidant protein NRF2 as playing a key role in the pathogenesis of this disorder. In addition to clarifying the mechanism of disease development, the authors demonstrated that pharmacologic induction of the NRF2 pathway slows the progression of disease in mouse models, suggesting a potential intervention for human patients. 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.