Diquat is an
herbicide that generates
superoxide anions through redox cycling. Nuclear factor erythroid-derived 2- like 2 (Nrf2) is a
transcription factor that up-regulates cytoprotective genes in response to oxidative stress. To investigate the protective effect of Nrf2 against
diquat-induced toxicity, wild-type, Nrf2-null and Kelch-like ECH-associated
protein 1-knockdown (Keap1-KD) mice with enhanced Nrf2 activity were treated with
diquat dibromide (125 mg/kg, i.p.). Blood and tissues were collected at 1, 2, 4 and 6 hours
after treatment. Administration of
diquat resulted in lipid peroxidation and lethality in wild-type mice, which were more in Nrf2-null mice and less in Keap1-KD mice.
Diquat produced liver injury in Nrf2-null mice, as evidenced by increased serum ALT activity and extensive hepatic
necrosis, but not in wild-type and Keap1-KD mice.
Diquat produced more severe
lung injury in Nrf2-null than in wild-type mice, as evidenced by increased lung weight and alveolar collapse. In contrast, Keap1-KD mice had attenuated lung
edema and no histopathological alterations. To further investigate the mechanism of the protective effects of Nrf2, lung and liver
glutathione (GSH) concentrations were quantified.
Diquat decreased GSH in lung and liver in wild-type mice, and the decrease was more in Nrf2-null mice, and less in Keap1-KD mice. After
diquat treatment, the
mRNA of the GSH synthesis
enzyme Gclc was increased in Keap1-KD, but not in Nrf2-null mice. Collectively, Nrf2 plays an important role in preventing
diquat-induced liver and
lung injury, and this protective effect results from Nrf2-regulated elevation of cellular GSH and expression of GSH synthetic genes.