Nrf2 activation prevents cadmium-induced acute liver injury.
Oxidative stress plays an important role in cadmium-induced liver injury. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that up-regulates cytoprotective genes in response to oxidative stress. To investigate the role of Nrf2 in cadmium-induced hepatotoxicity, Nrf2-null mice, wild-type mice, kelch-like ECH-associated protein 1-knockdown (Keap1-KD) mice with enhanced Nrf2, and Keap1-hepatocyte knockout (Keap1-HKO) mice with maximum Nrf2 activation were treated with cadmium chloride (3.5mg Cd/kg, i.p.). Blood and liver samples were collected 8h thereafter. Cadmium increased serum alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) activities, and caused extensive hepatic hemorrhage and necrosis in the Nrf2-null mice. In contrast, Nrf2-enhanced mice had lower serum ALT and LDH activities and less morphological alternations in the livers than wild-type mice. H(2)DCFDA (2',7'-dichlorodihydrofluoresein diacetate) staining of primary hepatocytes isolated from the four genotypes of mice indicated that oxidative stress was higher in Nrf2-null cells, and lower in Nrf2-enhanced cells than in wild-type cells. To further investigate the mechanism of the protective effect of Nrf2, mRNA of metallothionein (MT) and other cytoprotective genes were determined. Cadmium markedly induced MT-1 and MT-2 in livers of all four genotypes of mice. In contrast, genes involved in glutathione synthesis and reducing reactive oxygen species, including glutamate-cysteine ligase (Gclc), glutathione peroxidase-2 (Gpx2), and sulfiredoxin-1 (Srxn-1) were only induced in Nrf2-enhanced mice, but not in Nrf2-null mice. In conclusion, the present study shows that Nrf2 activation prevents cadmium-induced oxidative stress and liver injury through induction of genes involved in antioxidant defense rather than genes that scavenge Cd.
Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA.
Kai C
KC
Wu
Jie J
JJ
Liu
Curtis D
CD
Klaassen
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D002104:Cadmium / Q000633:toxicity*; D055785:Gene Knockdown Techniques; D005978:Glutathione / Q000097:blood; D022781:Hepatocytes / Q000187:drug effects; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008099:Liver / Q000737:chemistry / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000819:agonists*; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000032:analysis; D060888:Real-Time Polymerase Chain Reaction
D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D017382:Reactive Oxygen Species; D002104:Cadmium; D007770:L-Lactate Dehydrogenase; D000410:Alanine Transaminase; D005978:Glutathione