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Assessment of Mitochondrial Functions and Cell Viability in Renal Cells Overexpressing Protein Kinase C Isozymes
Published on: January 7, 2013
Assessment of cisplatin-induced nephrotoxicity by microarray technology
1Department of Toxicology, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, P.O. Box 368, Ridgefield, Connecticut 06877-0368, USA. qhuang@rdg.boeringer-ingelheim.com
Abstract:
Microarrays are a new technology used to study global gene expression and to decipher biological pathways. In the current study, microarrays were used to examine gene expression patterns associated with cisplatin-mediated nephrotoxicity. Sprague-Dawley rats received either single or seven daily ip doses of cisplatin (0.5 or 1 mg/kg/day) or the inactive isomer transplatin (1 or 3 mg/kg/day). Histopathological evaluation revealed renal proximal tubular necrosis in animals that received cisplatin for 7 days, but no hepatotoxic findings. Microarray analyses were performed using rat specific arrays containing 250 toxicity-related genes. Prominent gene expression changes were observed only in the kidneys of rats that received cisplatin for 7 days. Mechanistically, the gene expression pattern elicited by cisplatin (e.g., Bax upward arrow and SMP-30 downward arrow) suggested the occurrence of apoptosis and the perturbation of intracellular calcium homeostasis. The induction of multidrug resistance genes (MDR1 upward arrow, P-gp upward arrow) and tissue remodeling proteins (clusterin upward arrow, IGFBP-1 upward arrow, and TIMP-1 upward arrow) indicated the development of cisplatin resistance and tissue regeneration. Select gene expression changes were further confirmed by TaqMan analyses. Gene expression changes were not observed in the liver following cisplatin administration. In contrast to these in vivo findings, studies using NRK-52E kidney epithelial cells and clone-9 liver cells suggested that liver cells were more sensitive to cisplatin treatment. The discrepancies between the in vivo and in vitro results suggest that caution should be taken when extrapolating data from in vivo to in vitro systems. Nonetheless, the current study elucidates the biochemical pathways involved in cisplatin toxicity and demonstrates the utility of microarrays in toxicological studies.
Insights
Microarrays revealed cisplatin causes kidney damage and apoptosis in rats. This study highlights microarray utility in toxicology and cautions against direct extrapolation of in vitro to in vivo findings.
Area of Science:
- Toxicology
- Molecular Biology
- Genomics
Background:
- Cisplatin is a widely used chemotherapy agent with known nephrotoxicity.
- Understanding the molecular mechanisms of cisplatin-induced kidney damage is crucial for developing protective strategies.
- Microarray technology offers a powerful tool for global gene expression analysis in toxicological studies.
Purpose of the Study:
- To investigate gene expression patterns associated with cisplatin-mediated nephrotoxicity using microarrays.
- To elucidate the biochemical pathways involved in cisplatin toxicity in vivo and in vitro.
- To assess the utility of microarrays in toxicological research.
Main Methods:
- Sprague-Dawley rats were administered cisplatin or transplatin, and gene expression was analyzed using rat-specific toxicity arrays.
- Histopathological evaluation was performed to assess tissue damage.
- TaqMan analyses were used to confirm select gene expression changes.
- In vitro studies were conducted using NRK-52E kidney epithelial cells and clone-9 liver cells.
Main Results:
- Cisplatin administration for 7 days induced renal proximal tubular necrosis and significant gene expression changes in the kidney, but not the liver.
- Gene expression patterns suggested cisplatin triggers apoptosis and disrupts calcium homeostasis, while also inducing multidrug resistance and tissue regeneration markers.
- In vitro studies indicated liver cells were more sensitive to cisplatin than kidney cells, contrasting with in vivo findings.
Conclusions:
- Microarray analysis effectively identified molecular pathways involved in cisplatin nephrotoxicity, including apoptosis and cellular repair mechanisms.
- The study demonstrates the value of microarrays in toxicological research for deciphering complex biological responses.
- Discrepancies between in vivo and in vitro results emphasize the need for careful interpretation when extrapolating data between systems.
