Nrf2 Amplifies Oxidative Stress via Induction of Klf9

• DOI: 10.1016/j.molcel.2014.01.033
• Publication Date: 2014-03-07T23:46:11Z
• Authors: Shoshanna N. Zucker; Emily E. Fink; Archis Bagati; Sudha Mannava; Anna Bianchi-Smir...; Paul N. Bogner; Joseph A. Wawrzyniak; Colleen Foley; Katerina I. Leonova; Melissa J. Grimm; Kalyana Moparthy; Yurij Ionov; Jianmin Wang; Song Liu; Sandra Sexton; Eugene S. Kandel; Andrei V. Bakin; Yuesheng Zhang; Naftali Kaminski; Brahm H. Segal; Mikhail A. Nikiforov
• Keywords: 0301 basic medicine; Binding Sites; NF-E2-Related Factor 2; Pulmonary Fibrosis; Kruppel-Like Transcription Factors; Cell Biology; Bleomycin; Mice; Oxidative Stress; 03 medical and health sciences; Gene Expression Regulation; Genes, Reporter; Cell Line, Tumor; NIH 3T3 Cells; Animals; Humans; Luciferases; Promoter Regions, Genetic; Reactive Oxygen Species; Molecular Biology; Lung; Protein Binding; Signal Transduction

Reactive oxygen species (ROS) activate NF-E2-related transcription factor 2 (Nrf2), a key transcriptional regulator driving antioxidant gene expression and protection from oxidant injury. Here, we report that in response to elevation of intracellular ROS above a critical threshold, Nrf2 stimulates expression of transcription Kruppel-like factor 9 (Klf9), resulting in further Klf9-dependent increases in ROS and subsequent cell death. We demonstrated that Klf9 independently causes increased ROS levels in various types of cultured cells and in mouse tissues and is required for pathogenesis of bleomycin-induced pulmonary fibrosis in mice. Mechanistically, Klf9 binds to the promoters and alters the expression of several genes involved in the metabolism of ROS, including suppression of thioredoxin reductase 2, an enzyme participating in ROS clearance. Our data reveal an Nrf2-dependent feedforward regulation of ROS and identify Klf9 as a ubiquitous regulator of oxidative stress and lung injury.