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

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{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 7.5more » {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.« less

Authors:
 [1];  [2];  [3];  [4];  [3];  [4]
  1. 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). E-mail: rogersl@ccri.net
  2. Center for Cell and Vascular Biology, Columbus Children's Research Institute, Columbus, OH (United States)
  3. Center for Developmental Pharmacology and Toxicology, Columbus Children's Research Institute, Columbus, OH (United States)
  4. (United States)
Publication Date:
OSTI Identifier:
20850503
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 217; Journal 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)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ALANINES; BLOOD; CHICKENS; GLUTATHIONE; HISTOLOGY; IN VIVO; INJURIES; LIVER; MICE; NECROSIS; OXIDIZERS; TIME DEPENDENCE; TUBULES; UREA

Citation Formats

Rogers, Lynette K., Bates, Carlton M., Welty, Stephen E., Center for Perinatal Research, Columbus Children's Research Institute, Columbus, OH, Smith, Charles V., and Center for Developmental Pharmacology and Toxicology, Seattle Children's Hospital and Regional MediElsevier Inc.cal Center, Seattle, WA. Diquat induces renal proximal tubule injury in glutathione reductase-deficient mice. United States: N. p., 2006. Web. doi:10.1016/j.taap.2006.08.012.
Rogers, Lynette K., Bates, Carlton M., Welty, Stephen E., Center for Perinatal Research, Columbus Children's Research Institute, Columbus, OH, Smith, Charles V., & Center for Developmental Pharmacology and Toxicology, Seattle Children's Hospital and Regional MediElsevier Inc.cal Center, Seattle, WA. Diquat induces renal proximal tubule injury in glutathione reductase-deficient mice. United States. doi:10.1016/j.taap.2006.08.012.
Rogers, Lynette K., Bates, Carlton M., Welty, Stephen E., Center for Perinatal Research, Columbus Children's Research Institute, Columbus, OH, Smith, Charles V., and Center for Developmental Pharmacology and Toxicology, Seattle Children's Hospital and Regional MediElsevier Inc.cal Center, Seattle, WA. Fri . "Diquat induces renal proximal tubule injury in glutathione reductase-deficient mice". United States. doi:10.1016/j.taap.2006.08.012.
@article{osti_20850503,
title = {Diquat induces renal proximal tubule injury in glutathione reductase-deficient mice},
author = {Rogers, Lynette K. and Bates, Carlton M. and Welty, Stephen E. and Center for Perinatal Research, Columbus Children's Research Institute, Columbus, OH and Smith, Charles V. and Center for Developmental Pharmacology and Toxicology, Seattle Children's Hospital and Regional MediElsevier Inc.cal Center, Seattle, WA},
abstractNote = {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.},
doi = {10.1016/j.taap.2006.08.012},
journal = {Toxicology and Applied Pharmacology},
number = 3,
volume = 217,
place = {United States},
year = {Fri Dec 15 00:00:00 EST 2006},
month = {Fri Dec 15 00:00:00 EST 2006}
}