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Activation of NRF2 ameliorates oxidative stress and cystogenesis in autosomal dominant polycystic kidney disease

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.