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Nrf2-mediated enhancer activation ameliorates oxidative stress and cystogenesis in autosomal dominant polycystic kidney disease

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE141741 | GEO | 2021/01/26

REPOSITORIES: GEO

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Nrf2-mediated enhancer activation via phase separation ameliorates oxidative stress and cystogenesis in autosomal dominant polycystic kidney disease

Project description:Mitochondrial dysfunction is emerging as a crucial contributor to the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD), but the molecular mechanisms underlying the disturbed mitochondrial homeostasis in cystic cells remain elusive. In the present study, we identify impaired activity of NRF2 antioxidant pathway as a driver mechanism for mitochondrial dysfunction and ADPKD progression. Using a quantitative proteomic approach, we find that NRF2 antioxidant pathway is suppressed in ADPKD kidneys. In a cohort of ADPKD patients, reactive oxygen species (ROS) levels are frequently elevated, and the increased ROS levels inversely correlates with decreased NRF2 expression and positively correlates with disease severity. Genetic deletion of NRF2 increases ROS generation and promotes cyst growth in an orthologous ADPKD mouse model, while pharmacological induction of NRF2 reduces ROS levels and retards cystogenesis and disease progression. Mechanistically, NRF2 activates its antioxidant target genes mainly through remodeling enhancer landscapes. The activation domain of NRF2 forms phase-separated condensates with MED16, a Mediator complex subunit in vitro, and NRF2 is required for optimal Mediator recruitment to target genomic sites in vivo. Taken 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 mitochondrial homeostasis and combatting ADPKD.

2021-12-12 | PXD016312 | Pride

Nrf2-mediated enhancer activation ameliorates oxidative stress and cystogenesis in autosomal dominant polycystic kidney disease [ChIP-seq]

Project description: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. In the present study, we identify impaired activity of Nrf2 antioxidant pathway as a driver mechanism for oxidative damage and ADPKD progression. Using a quantitative proteomic approach, together with biochemistry analyses, we find that Nrf2 antioxidant pathway is suppressed due to increased degradation of Nrf2 protein in ADPKD kidneys. In a cohort of ADPKD patients, reactive oxygen species (ROS) levels are frequently elevated, and the ROS levels inversely correlates with Nrf2 abundance and positively correlates with disease severity. Genetic deletion of Nrf2 further increases ROS generation and promotes cyst growth in an orthologous ADPKD mouse model, while pharmacological induction of Nrf2 reduces ROS levels and retards cystogenesis and disease progression. Mechanistically, pharmacological induction of Nrf2 remodels enhancer landscapes and activates Nrf2-bound enhancer-associated genes in ADPKD cells. The activation domain of Nrf2 forms phase-separated condensates with Mediator subunit MED16 in vitro, and Nrf2 is required for optimal Mediator recruitment to target genomic loci in vivo. Taken 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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Nrf2-mediated enhancer activation ameliorates oxidative stress and cystogenesis in autosomal dominant polycystic kidney disease [RNA-seq]

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Project description:Nrf2-mediated enhancer activation ameliorates oxidative stress and cystogenesis in autosomal dominant polycystic kidney disease

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