Identification of putative gene based markers of renal toxicity.
- 1 March 2004
- journal article
- research article
- Published by Environmental Health Perspectives in Environmental Health Perspectives
- Vol. 112 (4), 465-479
- https://doi.org/10.1289/ehp.6683
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.Keywords
This publication has 77 references indexed in Scilit:
- Identification of platform-independent gene expression markers of cisplatin nephrotoxicity.Environmental Health Perspectives, 2004
- Toxicogenomics in risk assessment: an overview of an HESI collaborative research program.Environmental Health Perspectives, 2004
- Acute Renal Failure: Is Nitric Oxide the Bad Guy?Antioxidants and Redox Signaling, 2002
- Methapyrilene Toxicity: Anchorage of Pathologic Observations to Gene Expression AlterationsToxicologic Pathology, 2002
- Induction of Apoptosis by a Secreted Lipocalin That is Transcriptionally Regulated by IL-3 DeprivationScience, 2001
- Genomic Structure of the Human Plasma Prekallikrein Gene, Identification of Allelic Variants, and Analysis in End-Stage Renal DiseaseGenomics, 2000
- Ubiquitous localization of leukotriene A4 hydrolase in the rat nephronKidney International, 1999
- Human kallikrein gene delivery protects against gentamycin-induced nephrotoxicity in ratsKidney International, 1998
- Clusterin depletion enhances immune glomerular injury in the isolated perfused kidneyKidney International, 1994
- Purification and Chemical Characterization of β‐Trace Protein from Human Cerebrospinal Fluid: Its Identification as Prostaglandin D SynthaseJournal of Neurochemistry, 1993