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Rupesh P. Amin,¹ Alison E. Vickers,² Frank Sistare,³ Karol L. Thompson,³ Richard J. Roman,⁴ Michael Lawton,⁵ Jeffrey Kramer,⁵ Hisham K. Hamadeh,^1,6 Jennifer Collins,¹ Sherry Grissom,¹ Lee Bennett,¹ C. Jeffrey Tucker,¹ Stacie Wild,⁶ Clive Kind,⁷ Victor Oreffo,⁷ John W. Davis II,⁸ Sandra Curtiss,⁵ Jorge M. Naciff,⁹ Michael Cunningham,¹ Raymond Tennant,¹ James Stevens,¹⁰ Bruce Car,¹¹ Timothy A. Bertram,⁵ and Cynthia A. Afshari^1,6

¹National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA; ²Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA; ³Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Laurel, Maryland, USA; ⁴Medical College of Wisconsin and Physiogenix Inc., Milwaukee, Wisconsin, USA; ⁵Pfizer Inc, St. Louis, Missouri, USA, and Groton, Connecticut, USA; ⁶Amgen Inc., Thousand Oaks, California, USA; ⁷AstraZeneca Inc., Leicestershire, United Kingdom; ⁸Schering-Plough Research Institute, Lafayette, New Jersey, USA; ⁹The Procter & Gamble Company, Miami Valley Laboratories, Cincinnati, Ohio, USA; ¹⁰Eli Lilly and Company, Indianapolis, Indiana, USA; ¹¹Bristol-Myers Squibb Company, Wilmington, Delaware, USA

Abstract
This study, designed and conducted as part of the International Life Sciences Institute working group on the Application of Genomics and Proteomics, examined the changes in the expression profile of genes associated with the administration of three different nephrotoxicants--cisplatin, gentamicin, and puromycin--to assess the usefulness of microarrays in the understanding of mechanism(s) of nephrotoxicity. Male Sprague-Dawley rats were treated with daily doses of puromycin (5-20 mg/kg/day for 21 days) , gentamicin (2-240 mg/kg/day for 7 days) , or a single dose of cisplatin (0.1-5 mg/kg) . Groups of rats were sacrificed at various times after administration of these compounds for standard clinical chemistry, urine analysis, and histological evaluation of the kidney. RNA was extracted from the kidney for microarray analysis. Principal component analysis and gene expression-based clustering of compound effects confirmed sample separation based on dose, time, and degree of renal toxicity. In addition, analysis of the profile components revealed some novel changes in the expression of genes that appeared to be associated with injury in specific portions of the nephron and reflected the mechanism of action of these various nephrotoxicants. For example, although puromycin is thought to specifically promote injury of the podocytes in the glomerulus, the changes in gene expression after chronic exposure of this compound suggested a pattern similar to the known proximal tubular nephrotoxicants cisplatin and gentamicin ; this prediction was confirmed histologically. We conclude that renal gene expression profiling coupled with analysis of classical end points affords promising opportunities to reveal potential new mechanistic markers of renal toxicity. Key words: biomarkers, cisplatin, gentamicin, microarrays, nephrotoxicity, proximal tubule, puromycin, toxicogenomics. Environ Health Perspect 112:465-479 (2004) . doi:10.1289/txg.6683 available via http://dx.doi.org/ [Online 15 January 2004]

This article is part of the mini-monograph "Application of Genomics to Mechanism-Based Risk Assessment."

Address correspondence to C. Afshari, Amgen Inc., One Amgen Center Dr., MS 5-1-A, Thousand Oaks, CA 91320 USA. Telephone: (805) 447-3537. Fax: (805) 449-4687. E-mail: cafshari@amgen.com

We would like to thank the following people: J. Bonventure for donation of antibody reagents, and S. Pettit, S. Susanne, P. Bushel, and R. Paules for maintenance of and posting of data to the International Life Sciences Institute (ILSI) and the National Institute of Environmental Health Sciences web sites. Our appreciation to B. Pennie, D. Robinson, and R. Tyler for their leadership role in the establishment of this ILSI working group. We thank members of the Health and Environmental Health Sciences (HESI) Technical Committee on Application of Genomics to Mechanism-Based Risk Assessment for critically reviewing this manuscript prior to submission.

The authors declare they have no competing financial interests.

Received 18 August 2003 ; accepted 14 January 2004.

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