title: Nrf2 protects against diquat-induced liver and lung injury.
abstract: 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.
authors: Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors: Kai Connie
authors: KC
authors: Wu
authors: Youcai
authors: Y
authors: Zhang
authors: Curtis D
authors: CD
authors: Klaassen
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D004178:Diquat / Q000633:toxicity*; D005721:Glutamate-Cysteine Ligase / Q000096:biosynthesis; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D006540:Herbicides / Q000633:toxicity; D007178:Inbreeding; D055370:Lung Injury / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051267:NF-E2-Related Factor 2 / Q000172:deficiency / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D016019:Survival Analysis; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
chemical_list: D000975:Antioxidants; D006540:Herbicides; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D017392:Thiobarbituric Acid Reactive Substances; D004178:Diquat; D000410:Alanine Transaminase; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione; D019803:Glutathione Disulfide