Diquat induces renal proximal tubule injury in glutathione reductase-deficient mice
- Center for Developmental Pharmacology and Toxicology, Columbus Children's Research Institute, Columbus, OH (United States) and Center for Perinatal Research, Columbus Children's Research Institute, Columbus, OH (United States)
- Center for Cell and Vascular Biology, Columbus Children's Research Institute, Columbus, OH (United States)
- Center for Developmental Pharmacology and Toxicology, Columbus Children's Research Institute, Columbus, OH (United States)
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{sup 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 {mu}mol/kg of diquat, but no ALT elevations were observed in diquat-treated C3H/HeN mice for up to 6 h after 50 {mu}mol/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 {mu}mol/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 {mu}mol/g tissue at 0 and 50 {mu}mol/kg, respectively), and increases in renal GSSG levels were observed in the Neu mice as early as 0.5 h after 7.5 {mu}mol/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 {mu}mol/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.
- OSTI ID:
- 20850503
- Journal Information:
- Toxicology and Applied Pharmacology, Vol. 217, Issue 3; Other Information: DOI: 10.1016/j.taap.2006.08.012; PII: S0041-008X(06)00292-4; Copyright (c) 2006 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); ISSN 0041-008X
- Country of Publication:
- United States
- Language:
- English
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