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Toxicologic Pathology
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Molecular Mechanisms of Renal Tissue Repair in Survival from Acute Renal Tubule Necrosis: Role of ERK1/2 Pathway

Vishal S. Vaidya

Department of Toxicology, School of Pharmacy, The University of Louisiana at Monroe, Louisiana, USA

Kartik Shankar

Department of Toxicology, School of Pharmacy, The University of Louisiana at Monroe, Louisiana, USA

Edward A. Lock

Syngenta, Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire, UK

Darlene Dixon

Laboratory of Experimental Pathology, NIEHS, Research Triangle Park, North Carolina, USA

Harihara M. Mehendale

Department of Toxicology, School of Pharmacy, The University of Louisiana at Monroe, Louisiana, USA, mehendale{at}ulm.edu

Our earlier studies with S-(1,2-dichlorovinyl)-L-cysteine (DCVC) showed that prior administration of a low priming dose of 15 mg/kg, IP to mice, given 72 hours before administration of a normally lethal dose of DCVC (75 mg/kg, IP) led to renal tubule necrosis, however sustained renal tubule regeneration was observed and these mice recovered from renal failure and survived. The objective of the present study was to investigate the role of extracellular signal-regulated kinase (ERK) pathway in this autoprotection model. Following the priming dose of DCVC, IL-6 protein and mRNA increased markedly as early as 1 hour after dosing, peaking at 3 hours with a 1.5-fold increase in plasma. Immunocytochemistry on kidney sections using specific antibodies against TGF-{alpha}, HB-EGF, EGFr, IGF-1R β, Grb-2, and phospho-p44/42 MAP kinase (ERK1/2) revealed a significantly higher staining of these molecules 3 to 72 hours after dosing, indicating up regulation of the ERK pathway. Following a lethal dose of DCVC (75 mg/kg) the early increase in these signaling molecules was not sustained, being markedly reduced 24 and 36 hours after dosing, leading to inhibition of S-phase DNA synthesis, cell division and renal tubule repair. In contrast, prior treatment with a low dose of DCVC, followed by a high dose led to a sustained stimulation of the renal ERK pathway, renal tubule regeneration and recovery from acute renal failure. These results suggest that a sustained activation of the ERK1/2 pathway may be a key factor in enabling a continued renal tubule repair and hence protection from the progressive phase of DCVC-induced acute renal tubular necrosis in the mouse.

Key Words: Renal tubular necrosis • cytokines • ERK1/2 pathway • tissue repair • growth factors • nephrotoxicity.

References

Toxicologic Pathology, Vol. 31, No. 6, 604-618 (2003)
DOI: 10.1080/01926230390241945
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This Article
Right arrow Abstract Freely available
Right arrow Free Full Text (Free PDF) Free
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
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Right arrow Email this article to a friend
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Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Saved Citations
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Request Reprints
Right arrow Add to My Marked Citations
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Right arrow Citing Articles via Scopus
Google Scholar
Right arrow Articles by Vaidya, V. S.
Right arrow Articles by Mehendale, H. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Vaidya, V. S.
Right arrow Articles by Mehendale, H. M.
Right arrowPubmed/NCBI databases
*Compound via MeSH
*Substance via MeSH
Hazardous Substances DB
*CYSTEINE
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