Nrf2 activation prevents cadmium-induced acute liver injury

Toxicol Appl Pharmacol. 2012 Aug 15;263(1):14-20. doi: 10.1016/j.taap.2012.05.017. Epub 2012 Jun 4.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alanine Transaminase / blood
  • Animals
  • Cadmium / toxicity*
  • Gene Knockdown Techniques
  • Glutathione / blood
  • Hepatocytes / drug effects
  • L-Lactate Dehydrogenase / blood
  • Liver / chemistry
  • Liver / drug effects*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NF-E2-Related Factor 2 / agonists*
  • Oxidative Stress / drug effects
  • Reactive Oxygen Species / analysis
  • Real-Time Polymerase Chain Reaction

Substances

  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • Reactive Oxygen Species
  • Cadmium
  • L-Lactate Dehydrogenase
  • Alanine Transaminase
  • Glutathione