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ToxSci Advance Access originally published online on October 16, 2008
Toxicological Sciences 2009 107(1):258-269; doi:10.1093/toxsci/kfn203
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Published by Oxford University Press 2008.
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org.

Gene Expression Analysis Reveals New Possible Mechanisms of Vancomycin-Induced Nephrotoxicity and Identifies Gene Markers Candidates

Christine Dieterich1,2, Angela Puey, Sylvia Lyn, Robert Swezey, Anna Furimsky, David Fairchild, Jon C. Mirsalis and Hanna H. Ng

Biosciences Division, SRI International, 333 Ravenswood Avenue, Menlo Park, California 94025-3493

1 To whom correspondence should be addressed. Fax: +46-8-30-34-23. E-mail: chris_diet{at}yahoo.com.

Received July 18, 2008; accepted September 19, 2008


  Abstract

Vancomycin, one of few effective treatments against methicillin-resistant Staphylococcus aureus, is nephrotoxic. The goals of this study were to (1) gain insights into molecular mechanisms of nephrotoxicity at the genomic level, (2) evaluate gene markers of vancomycin-induced kidney injury, and (3) compare gene expression responses after iv and ip administration. Groups of six female BALB/c mice were treated with seven daily iv or ip doses of vancomycin (50, 200, and 400 mg/kg) or saline, and sacrificed on day 8. Clinical chemistry and histopathology demonstrated kidney injury at 400 mg/kg only. Hierarchical clustering analysis revealed that kidney gene expression profiles of all mice treated at 400 mg/kg clustered with those of mice administered 200 mg/kg iv. Transcriptional profiling might thus be more sensitive than current clinical markers for detecting kidney damage, though the profiles can differ with the route of administration. Analysis of transcripts whose expression was changed by at least twofold compared with vehicle saline after high iv and ip doses of vancomycin suggested the possibility of oxidative stress and mitochondrial damage in vancomycin-induced toxicity. In addition, our data showed changes in expression of several transcripts from the complement and inflammatory pathways. Such expression changes were confirmed by relative real-time reverse transcription–polymerase chain reaction. Finally, our results further substantiate the use of gene markers of kidney toxicity such as KIM-1/Havcr1, as indicators of renal injury.

Key Words: vancomycin; route of administration; nephrotoxicity; gene expression; inflammation; complement pathway activation.

2 Present address: Lipopeptide AB, Fogdevreten 2B, 17177 Stockholm, Sweden.


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