Diquat induces renal proximal tubule injury in glutathione reductase-deficient mice.
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.
Rogers
Lynette K
LK
Center for Developmental Pharmacology and Toxicology, Columbus Children's Research Institute, Columbus, OH 43205, USA. rogersl@ccri.net
Bates
Carlton M
CM
Welty
Stephen E
SE
Smith
Charles V
CV
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001806:Blood Urea Nitrogen; D003404:Creatinine / Q000097:blood; D004178:Diquat / Q000633:toxicity*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000378:metabolism; D005980:Glutathione Reductase / Q000172:deficiency* / Q000235:genetics; D006540:Herbicides / Q000633:toxicity*; D007150:Immunohistochemistry; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D009336:Necrosis / Q000139:chemically induced / Q000473:pathology
D006540:Herbicides; D004178:Diquat; D003404:Creatinine; D005980:Glutathione Reductase; D000410:Alanine Transaminase; D005978:Glutathione