ToxSci Advance Access originally published online on May 2, 2003
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Toxicological Sciences 74, 215-227 (2003)
Copyright © 2003 by the Society of Toxicology
SYSTEMS TOXICOLOGY |
Role of Tissue Repair in Survival from S-(1,2-Dichlorovinyl)-L-Cysteine–Induced Acute Renal Tubular Necrosis in the Mouse
* Department of Toxicology, School of Pharmacy, The University of Louisiana at Monroe, 700 University Avenue, Sugar Hall, Room 306, Monroe, Louisiana 71209-0470;
Syngenta, Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire SK 104TJ, United Kingdom; and
Pathology Associates International, National Center for Toxicological Research, Jefferson, Arkansas 72079
S-(1,2-Dichlorovinyl)-L-cysteine (DCVC), a model nephrotoxicant in mice, causes acute tubular necrosis and death at high doses. Our earlier studies revealed that renal tissue repair was critical for survival in mice with DCVC nephrotoxicity. The objective of this study was to investigate if increasing renal tissue repair could protect mice from the lethal outcome of DCVC. Male Swiss Webster (SW) mice were administered a low dose of DCVC (15 mg/kg, ip) 72 h before injection of a normally lethal dose of DCVC (75 mg/kg, ip); this resulted in 100% protection against the lethal effect of DCVC. Because DCVC caused ~twofold decrease in cytosolic and mitochondrial ß-lyase activity, the possibility that DCVC protection may be caused by decreased bioactivation was examined. Mercuric chloride (HgCl2, 6 mg/kg), a nephrotoxicant with no effect on ß-lyase activity, was administered 96 h before a lethal dose of DCVC. This also resulted in 100% protection from the lethal effect of DCVC. In both studies total glutathione was unchanged at any time after the lethal dose of DCVC was administered, obviating the role of glutathione in protection. In both cases the augmented and sustained tissue repair induced by priming dose and documented by 3H-thymidine pulse labeling and immunocytochemistry for proliferating cell nuclear antigen resulted in 100% survival in spite of the extensive renal injury. These findings suggest that stimulation of renal tubular repair by the priming dose, through augmented cell division, and the resistance of new cells to mechanisms of progression of injury, underlies auto- and heteroprotection against DCVC. The molecular mechanisms may have potential application in pharmacotherapeutic intervention for treatment of acute renal failure.
Key Words: ß-lyase; DCVC; mercuric chloride; protection; renal injury; tissue repair.
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