Nrf2 Amplifies Oxidative Stress via Induction of Klf9

Abstract

Summary 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 feed-forward regulation of ROS and identify Klf9 as a novel ubiquitous regulator of oxidative stress and lung injury.

Keap1 modulates the redox cycle and hepatocyte cell cycle in regenerating liver

“…They demonstrated that when intracellular ROS level elevates above a critical threshold, Nrf2 stimulates Klf9 expression, leading to amplification of oxidative stress and thereby cell death. 23 We found that hepatic Klf9 expression did not exhibit significant PH-dependent changes in Keap1+/+ mice and there was no significant differences in Klf9 mRNA levels between Keap1+/+ and Keap1+/− mice after PH. The data suggest that although hepatic Nrf2 was activated after 36 h post-PH due to Keap1 knockdown, Nrf2 activity did not surpass a threshold leading to Klf9 upregulation.…”

Using Sensors and Generators of H2O2to Elucidate the Toxicity Mechanism of Piperlongumine and Phenethyl Isothiocyanate

“…However, increasing NRF-2 does not always exert a protective function on the intracellular oxidant level. A recent study showed that increasing NRF-2 level above a threshold actually amplifies oxidative stress by induction of KLF9 and causes additional cellular toxicity, and so, a balance of its pro-oxidant and antioxidant function has to be considered (58).…”

Hydrogen peroxide prevents vascular calcification induced ROS production by regulating Nrf-2 pathway

“…15 However, Zucker et al found that hydrogen peroxide on dosage more than 0.05 mM could increase the expression of Kruppel-like factor 9 (Klf9) and induce cell death by ROS accumulation, whereas hydrogen peroxide on dosage less than 0.05 mM had no effect on cell survival and activated Nrf-2-ARE pathway to clear intracellular ROS to keep the redox equilibrium in cells. 18 To elucidate the effect of hydrogen peroxide on RASMCs, we pretreated RASMCs with hydrogen peroxide at different concentrations (0.01 mM, 0.02 mM, 0.05 mM, and 0.08 mM) for 2 h. During the 48-h incubation with calcification medium, we observed that hydrogen peroxide on dosage more than 0.01 mM could inhibit RASMCs survival, whereas hydrogen peroxide on dosage of 0.01 mM had no effect on cell survival. Then our current study focused on the effect of 0.01 mM hydrogen peroxide on RASMC calcification.…”