Document Detail

Molecular mechanisms of enhanced renal cell division in protection against S-1,2-dichlorovinyl-L-cysteine-induced acute renal failure and death.
MedLine Citation:
PMID:  15741605     Owner:  NLM     Status:  MEDLINE    
Sustained activation of ERK 1/2 by a low dose (15 mg/kg ip) of S-1,2-dichlorovinyl-l-cysteine (DCVC) 72 h before administration of a lethal dose of DCVC (75 mg/kg ip) enhances renal cell division and protects mice against acute renal failure (ARF) and death (autoprotection). The objective of this study was to determine correlation among extent of S-phase DNA synthesis, activation of transcription factors, expression of G(1)/S cyclins, cyclin-dependent kinases (CDKs), and CDK inhibitors downstream of ERK 1/2 following DCVC-induced ARF in autoprotection. Administration of the lethal dose alone caused a general downregulation or an unsustainable increase, in transcriptional and posttranscriptional events thereby preventing G(1)-S transition of renal cell cycle. Phosphorylation of IkappaBalpha was inhibited resulting in limited nuclear translocation of NF-kappaB. However, cyclin D1 expression was high probably due to transcriptional cooperation of AP-1. Cyclin D1/cyclin-dependent kinase 4 (cdk4)-cdk6 system-mediated phosphorylation of retinoblastoma protein was downregulated due to overexpression of p16 at 24 h after exposure to the lethal dose alone. Inhibition of S-phase stimulation was confirmed by proliferating cell nuclear antigen assay (PCNA). This inhibitory response was prevented if the lethal dose was administered 72 h after the low priming dose of DCVC due to promitogenic effect of the low dose. NF-kappaB-DNA binding is not limited if mice were pretreated with the priming dose. Cyclin D1/cdk4-cdk6 expression stimulated by the priming dose of DCVC was unaltered even after the lethal dose in the autoprotected group, explaining higher phosphorylated-pRB and S-phase stimulation found in this group. These results were corroborated with PCNA immunohistochemistry. These findings suggest that the priming dose relieves the block on compensatory tissue repair by upregulation of promitogenic mechanisms, normally blocked by the high dose when administered without the prior priming dose.
Midhun C Korrapati; Edward A Lock; Harihara M Mehendale
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.     Date:  2005-03-01
Journal Detail:
Title:  American journal of physiology. Renal physiology     Volume:  289     ISSN:  1931-857X     ISO Abbreviation:  Am. J. Physiol. Renal Physiol.     Publication Date:  2005 Jul 
Date Detail:
Created Date:  2005-06-13     Completed Date:  2005-07-11     Revised Date:  2011-04-28    
Medline Journal Info:
Nlm Unique ID:  100901990     Medline TA:  Am J Physiol Renal Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  F175-85     Citation Subset:  IM    
Dept. of Toxicology, School of Pharmacy, College of Health Sciences, The University of Louisiana at Monroe, LA 71209-0470, USA.
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MeSH Terms
Acute Kidney Injury / chemically induced*,  physiopathology*
Cysteine / analogs & derivatives*,  toxicity*
DNA Replication
Dose-Response Relationship, Drug
Extracellular Signal-Regulated MAP Kinases / physiology
G1 Phase / drug effects*,  physiology
Kidney / physiology
S Phase / drug effects*,  physiology
Grant Support
Reg. No./Substance:
52-90-4/Cysteine; 627-72-5/S-(1,2-dichlorovinyl)cysteine; EC Signal-Regulated MAP Kinases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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