Diquat induces renal proximal tubule injury in glutathione reductase-deficient mice

Toxicol Appl Pharmacol. 2006 Dec 15;217(3):289-98. doi: 10.1016/j.taap.2006.08.012. Epub 2006 Sep 26.

Abstract

Reactive oxygen species (ROS) have been associated with many human diseases, and glutathione (GSH)-dependent processes are pivotal in limiting tissue damage. To test the hypothesis that Gr1(a1Neu) (Neu) mice, which do not express glutathione reductase (GR), would be more susceptible than are wild-type mice to ROS-mediated injury, we studied the effects of diquat, a redox cycling toxicant. Neu mice exhibited modest, dose- and time-dependent elevations in plasma alanine aminotransferase (ALT) activities, 126+/-36 U/l at 2 h after 5 micromol/kg of diquat, but no ALT elevations were observed in diquat-treated C3H/HeN mice for up to 6 h after 50 micromol/kg of diquat. Histology indicated little or no hepatic necrosis in diquat-treated mice of either strain, but substantial renal injury was observed in diquat-treated Neu mice, characterized by brush border sloughing in the proximal tubules by 1 h and tubular necrosis by 2 h after doses of 7.5 micromol/kg. Decreases in renal GSH levels were observed in the Neu mice by 2 h post dose (3.4+/-0.4 vs 0.2+/-0.0 micromol/g tissue at 0 and 50 micromol/kg, respectively), and increases in renal GSSG levels were observed in the Neu mice as early as 0.5 h after 7.5 micromol/kg (105.5+/-44.1 vs 27.9+/-4.8 nmol/g tissue). Blood urea nitrogen levels were elevated by 2 h in Neu mice after doses of 7.5 micromol/kg (Neu vs C3H, 32.8+/-4.1 vs 17.9+/-0.3 mg/dl). Diquat-induced renal injury in the GR-deficient Neu mice offers a useful model for studies of ROS-induced renal necrosis and of the contributions of GR in defense against oxidant-mediated injuries in vivo.

MeSH terms

  • Alanine Transaminase / blood
  • Animals
  • Blood Urea Nitrogen
  • Creatinine / blood
  • Diquat / toxicity*
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Glutathione / metabolism
  • Glutathione Reductase / deficiency*
  • Glutathione Reductase / genetics
  • Herbicides / toxicity*
  • Immunohistochemistry
  • Kidney / drug effects
  • Kidney / metabolism
  • Kidney / pathology
  • Kidney Diseases / chemically induced*
  • Kidney Diseases / metabolism
  • Kidney Diseases / pathology
  • Kidney Tubules, Proximal / drug effects*
  • Kidney Tubules, Proximal / metabolism
  • Kidney Tubules, Proximal / pathology
  • Liver / drug effects
  • Liver / pathology
  • Male
  • Mice
  • Mice, Inbred C3H
  • Mice, Knockout
  • Necrosis / chemically induced
  • Necrosis / pathology

Substances

  • Herbicides
  • Diquat
  • Creatinine
  • Glutathione Reductase
  • Alanine Transaminase
  • Glutathione