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This Article Full Text Full Text (PDF) All Versions of this Article: 289/1/F175    most recent 00418.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (9) Citing Articles via Google Scholar Google Scholar Articles by Korrapati, M. C. Articles by Mehendale, H. M. Search for Related Content PubMed PubMed Citation Articles by Korrapati, M. C. Articles by Mehendale, H. M.

Molecular mechanisms of enhanced renal cell division in protection against S-1,2-dichlorovinyl-L-cysteine-induced acute renal failure and death

¹Department of Toxicology, School of Pharmacy, College of Health Sciences, The University of Louisiana at Monroe, Monroe, Louisiana; and ²Department of Pharmaceutical Sciences, Medical University of South Carolina, Charleston, South Carolina

Submitted 23 November 2004 ; accepted in final form 27 February 2005

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 G₁/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 G₁-S transition of renal cell cycle. Phosphorylation of IB was inhibited resulting in limited nuclear translocation of NF-B. 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-B-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.

cyclin D1; extracellular signal-regulated kinases 1/2; phospho-retinoblastoma; tissue repair

This article has been cited by other articles:

				M. C. Korrapati, J. Chilakapati, F. A. Witzmann, C. Rao, E. A. Lock, and H. M. Mehendale Proteomics of S-(1, 2-dichlorovinyl)-L-cysteine-induced acute renal failure and autoprotection in mice Am J Physiol Renal Physiol, October 1, 2007; 293(4): F994 - F1006. [Abstract] [Full Text] [PDF]

				M. C. Korrapati, J. Chilakapati, E. A. Lock, J. R. Latendresse, A. Warbritton, and H. M. Mehendale Preplaced cell division: a critical mechanism of autoprotection against S-1,2-dichlorovinyl-L-cysteine-induced acute renal failure and death in mice Am J Physiol Renal Physiol, August 1, 2006; 291(2): F439 - F455. [Abstract] [Full Text] [PDF]