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Title: Diabetic mice are protected from normally lethal nephrotoxicity of S-1,2-dichlorovinyl-L-cysteine (DCVC): role of nephrogenic tissue repair

Abstract

Streptozotocin (STZ)-induced diabetic (DB) rats are protected from nephrotoxicity of gentamicin, cisplatin and mercuric chloride, although the mechanisms remain unclear. Ninety percent of DB mice receiving a LD90 dose (75 mg/kg, ip) of S-1,2-dichlorovinyl-L-cysteine (DCVC) survived in contrast to only 10% of the nondiabetic (NDB) mice surviving the same dose. We tested the hypothesis that the mechanism of protection is upregulated tissue repair. In the NDB mice, DCVC produced steep temporal increases in blood urea nitrogen (BUN) and plasma creatinine, which were associated with proximal tubular cell (PTC) necrosis, acute renal failure (ARF), and death within 48 h. In contrast, in the DB mice, BUN and creatinine increased less steeply, declining after 36 h to completely resolve by 96 h. HPLC analysis of plasma and urine revealed that DB did not alter the toxicokinetics of DCVC. Furthermore, activity of renal cysteine conjugate {beta}-lyase, the enzyme that bioactivates DCVC, was unaltered in DB mice, undermining the possibility of lower bioactivation of DCVC leading to lower injury. [3H]-thymidine pulse labeling and PCNA analysis indicated an early onset and sustained nephrogenic tissue repair in DCVC-treated DB mice. BRDU immunohistochemistry revealed a fourfold increase in the number of cells in S-phase in the DBmore » kidneys even without exposure to DCVC. Blocking the entry of cells into S-phase by antimitotic intervention using colchicine abolished stimulated nephrogenic tissue repair and nephroprotection. These findings suggest that preplacement of S-phase cells in the kidney due to diabetes is critical in mitigating the progression of DCVC-initiated renal injury by upregulation of tissue repair, leading to survival of the DB mice by avoiding acute renal failure.« less

Authors:
 [1];  [1];  [2];  [3];  [3];  [4]
  1. Department of Toxicology, College of Pharmacy, The University of Louisiana at Monroe, 700 University Avenue, Monroe, LA 71209-0470 (United States)
  2. Department of Pharmaceutical Sciences, Medical University of South Carolina, Charleston, SC 29425 (United States)
  3. Toxicologic Pathology Associates, National Center for Toxicological Research, Jefferson, AR 7207 (United States)
  4. Department of Toxicology, College of Pharmacy, The University of Louisiana at Monroe, 700 University Avenue, Monroe, LA 71209-0470 (United States). E-mail: mehendale@ulm.edu
Publication Date:
OSTI Identifier:
20783437
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 211; Journal Issue: 2; Other Information: DOI: 10.1016/j.taap.2005.07.015; PII: S0041-008X(05)00418-7; Copyright (c) 2005 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; BIOLOGICAL REPAIR; BLOOD; BUDR; COLCHICINE; CREATININE; CYSTEINE; EOSIN; HEMATOXYLIN; HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY; KIDNEYS; MICE; NECROSIS; PERCHLORIC ACID; RATS; STREPTOZOCIN; THYMIDINE; UREA

Citation Formats

Dnyanmote, Ankur V., Sawant, Sharmilee P., Lock, Edward A., Latendresse, John R., Warbritton, Alan A., and Mehendale, Harihara M. Diabetic mice are protected from normally lethal nephrotoxicity of S-1,2-dichlorovinyl-L-cysteine (DCVC): role of nephrogenic tissue repair. United States: N. p., 2006. Web. doi:10.1016/j.taap.2005.07.015.
Dnyanmote, Ankur V., Sawant, Sharmilee P., Lock, Edward A., Latendresse, John R., Warbritton, Alan A., & Mehendale, Harihara M. Diabetic mice are protected from normally lethal nephrotoxicity of S-1,2-dichlorovinyl-L-cysteine (DCVC): role of nephrogenic tissue repair. United States. doi:10.1016/j.taap.2005.07.015.
Dnyanmote, Ankur V., Sawant, Sharmilee P., Lock, Edward A., Latendresse, John R., Warbritton, Alan A., and Mehendale, Harihara M. Wed . "Diabetic mice are protected from normally lethal nephrotoxicity of S-1,2-dichlorovinyl-L-cysteine (DCVC): role of nephrogenic tissue repair". United States. doi:10.1016/j.taap.2005.07.015.
@article{osti_20783437,
title = {Diabetic mice are protected from normally lethal nephrotoxicity of S-1,2-dichlorovinyl-L-cysteine (DCVC): role of nephrogenic tissue repair},
author = {Dnyanmote, Ankur V. and Sawant, Sharmilee P. and Lock, Edward A. and Latendresse, John R. and Warbritton, Alan A. and Mehendale, Harihara M.},
abstractNote = {Streptozotocin (STZ)-induced diabetic (DB) rats are protected from nephrotoxicity of gentamicin, cisplatin and mercuric chloride, although the mechanisms remain unclear. Ninety percent of DB mice receiving a LD90 dose (75 mg/kg, ip) of S-1,2-dichlorovinyl-L-cysteine (DCVC) survived in contrast to only 10% of the nondiabetic (NDB) mice surviving the same dose. We tested the hypothesis that the mechanism of protection is upregulated tissue repair. In the NDB mice, DCVC produced steep temporal increases in blood urea nitrogen (BUN) and plasma creatinine, which were associated with proximal tubular cell (PTC) necrosis, acute renal failure (ARF), and death within 48 h. In contrast, in the DB mice, BUN and creatinine increased less steeply, declining after 36 h to completely resolve by 96 h. HPLC analysis of plasma and urine revealed that DB did not alter the toxicokinetics of DCVC. Furthermore, activity of renal cysteine conjugate {beta}-lyase, the enzyme that bioactivates DCVC, was unaltered in DB mice, undermining the possibility of lower bioactivation of DCVC leading to lower injury. [3H]-thymidine pulse labeling and PCNA analysis indicated an early onset and sustained nephrogenic tissue repair in DCVC-treated DB mice. BRDU immunohistochemistry revealed a fourfold increase in the number of cells in S-phase in the DB kidneys even without exposure to DCVC. Blocking the entry of cells into S-phase by antimitotic intervention using colchicine abolished stimulated nephrogenic tissue repair and nephroprotection. These findings suggest that preplacement of S-phase cells in the kidney due to diabetes is critical in mitigating the progression of DCVC-initiated renal injury by upregulation of tissue repair, leading to survival of the DB mice by avoiding acute renal failure.},
doi = {10.1016/j.taap.2005.07.015},
journal = {Toxicology and Applied Pharmacology},
number = 2,
volume = 211,
place = {United States},
year = {Wed Mar 01 00:00:00 EST 2006},
month = {Wed Mar 01 00:00:00 EST 2006}
}