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Identification of platform-independent gene expression markers of cisplatin nephrotoxicity
Karol L Thompson1, Cynthia A Afshari, Rupesh P Amin
1Center for Drug Evaluation and Research, Division of Applied Pharmacology Research, U.S. Food and Drug Administration, 10903 New Hampshire Avenue, Life Sciences Building 64, Silver Spring, MD 20993, USA. Thompsonk@cder.fda.gov
Abstract:
Within the International Life Sciences Institute Committee on Genomics, a working group was formed to focus on the application of microarray technology to preclinical assessments of drug-induced nephrotoxicity. As part of this effort, Sprague-Dawley rats were treated with the nephrotoxicant cisplatin at doses of 0.3-5 mg/kg over a 4- to 144-hr time course. RNA prepared from these animals was run on a variety of microarray formats at multiple sites. A set of 93 differentially expressed genes associated with cisplatin-induced renal injury was identified on the National Institute of Environmental Health Sciences (NIEHS) custom cDNA microarray platform using quadruplicate measurements of pooled animal RNA. The reproducibility of this profile of statistically significant gene changes on other platforms, in pooled and individual animal replicate samples, and in an independent study was investigated. A good correlation in response between platforms was found among the 48 genes in the NIEHS data set that could be matched to probes on the Affymetrix RGU34A array by UniGene identifier or sequence alignment. Similar results were obtained with genes that could be linked between the NIEHS and Incyte or PHASE-1 arrays. The degree of renal damage induced by cisplatin in individual animals was commensurate with the number of differentially expressed genes in this data set. These results suggest that gene profiles linked to specific types of tissue injury or mechanisms of toxicity and identified in well-performed replicated microarray experiments may be extrapolatable across platform technologies, laboratories, and in-life studies.
Insights
Microarray gene expression profiles accurately identify drug-induced kidney injury in rats. These profiles are reproducible across different platforms and studies, aiding in toxicity assessments.
Area of Science:
- Toxicology
- Genomics
- Biotechnology
Background:
- Drug-induced nephrotoxicity is a significant concern in preclinical assessments.
- Microarray technology offers a powerful tool for understanding cellular responses to toxicants.
Purpose of the Study:
- To evaluate the reproducibility of gene expression profiles in cisplatin-induced nephrotoxicity across different microarray platforms.
- To assess the correlation between gene expression changes and the degree of renal damage.
Main Methods:
- Sprague-Dawley rats were treated with cisplatin at varying doses and time points.
- RNA was extracted and analyzed using multiple microarray platforms (NIEHS, Affymetrix, Incyte, PHASE-1).
- Gene expression data was analyzed for differentially expressed genes and correlated with renal damage.
Main Results:
- A set of 93 differentially expressed genes associated with cisplatin-induced renal injury was identified.
- Good correlation was observed for matched genes across different microarray platforms.
- The number of differentially expressed genes correlated with the severity of cisplatin-induced renal damage.
Conclusions:
- Gene expression profiles identified using microarrays are reproducible across platforms, laboratories, and studies.
- These gene profiles can serve as reliable biomarkers for specific tissue injury and toxicity mechanisms.
- Microarray technology is a valuable tool for preclinical drug safety assessment.
