Activation of NRF2 ameliorates oxidative stress and cystogenesis in autosomal dominant polycystic kidney disease
Yi Lu, Yi Lu, Yongzhan Sun, Zhiheng Liu, Yumei Lu, Yumei Lu, Xu Zhu, Bingxue Lan, Zeyun Mi, Lin Dang, Na Li, Wenlei Zhan, Lu Tan, Jingbo Pi, Hui Xiong, Lirong Zhang, Yupeng Chen
Abstract
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.