Nrf2 protects against As(III)-induced damage in mouse liver and bladder

Abstract

Arsenic compounds are classified as toxicants and human carcinogens. Environmental exposure to arsenic imposes a big health issue worldwide. Arsenic elicits its toxic efforts through many mechanisms, including generation of reactive oxygen species (ROS). Nrf2 is the primary transcription factor that controls expression of a main cellular antioxidant response, which is required for neutralizing ROS and thus defending cells from exogenous insults. Previously, we demonstrated a protective role of Nrf2 against arsenic-induced toxicity using a cell culture model. In this report, we present evidence that Nrf2 protects against liver and bladder injury in response to six-weeks of arsenic exposure in a mouse model. Nrf2 −/− mice displayed more severe pathological changes in the liver and bladder, compared to Nrf2 +/+ mice. Furthermore, Nrf2 −/− mice were more sensitive to arsenic-induced DNA hypomethylation, oxidative DNA damage, and apoptotic cell death. These results indicate a protective role of Nrf2 against arsenic toxicity in vivo. Hence, this work demonstrates the feasibility of using dietary compounds that target activation of the Nrf2 signaling pathway to alleviate arsenic-induced damage.

Tanshinone I Activates the Nrf2-Dependent Antioxidant Response and Protects Against As(III)-Induced Lung Inflammation In Vitro and In Vivo

“…6). These results are coherent with our previous study demonstrating that in mice given drinking water contaminated with As(III), lung inflammation occurred irrespective of Nrf2 genotype (25). The reason that Nrf2 + / + mice did not show reduced inflammation compared to Nrf2…”

“…We and others have also demonstrated the interventional potential of diet-derived Nrf2 activators including sulforaphane (SF), lipoic acid, and cinnamaldehyde for the suppression of As(III) cytotoxicity through modulation of the Nrf2-dependent cellular defense mechanism (15,23,48,53,56). For example, SF has been shown to limit organ toxicity of As(III) in vivo when As(III) was administered through drinking water (25). More recently, we have shown that Nrf2 status determines the sensitivity of mice to As(III)-induced lung damage and that Nrf2 modulation using SF prevents inflammatory tissue damage in an in vivo As(III) inhalation model that is relevant to low environmental human exposure to As(III)-containing dusts (62).…”

“…The transcription factor Nrf2 is thought to control tissue damage from environmental insults by upregulating the expression of genes involved in antioxidant response and xenobiotic metabolism (20,25,26,59). Nrf2 is negatively regulated by Kelch-like ECH-associated protein-1 (Keap1), which forms an E3 ubiquitin ligase complex with Cullin 3 (Cul3) and Rbx1 (61).…”

“…In addition, reduced expression of Keap1, due to hypermethylation or loss of heterozygosity, also leads to high basal levels of Nrf2 in certain cancers (32,44). As(III) itself is an Nrf2 activator and has been shown to induce the Nrf2 pathway in many cell lines in vitro and in the liver, bladder, and lung when As(III) was administered through drinking water or inhaled particles in vivo (25,33,62). It is perplexing how could both beneficial chemopreventive compounds and harmful arsenicals induce Nrf2.…”

Nrf2 pathway activation contributes to anti-fibrosis effects of ginsenoside Rg1 in a rat model of alcohol- and CCl4-induced hepatic fibrosis

“…The upregulation of many antioxidant enzymes in the liver is mediated by Nrf2. Several studies have shown that Nrf2 plays a protective role in CCl 4 -induced liver fibrosis by regulating the antioxidant enzyme activity and the expression of down-stream genes [11][12][13] .…”