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Assessment of Mitochondrial Functions and Cell Viability in Renal Cells Overexpressing Protein Kinase C Isozymes
Published on: January 7, 2013
Cyclosporin-A induced toxicity in rat renal collecting duct cells: interference with enhanced hypertonicity induced
Laura K Schenk1, Markus M Rinschen, Jens Klokkers
1Department of Internal Medicine D, Experimental Nephrology, University of Muenster, Muenster, Germany.
Background/Aims:
Rat renal inner medullary collecting duct (IMCD) cells are physiologically exposed to a wide range of ambient tonicity. To maintain their function upon changes in osmolality, IMCD cells induce expression of osmoprotective and antiapoptotic genes, mainly mediated by the transcription factor Tonicity Enhancer Binding Protein (TonEBP). Some drugs like Cyclosporin-A (CsA) are discussed to interfere with the activity of TonEBP and thereby mediate their nephrotoxic effects. The aim of our study was to further understand CsA toxicity during elevation of ambient osmolality.
Methods:
First we examined cytotoxicity of CsA in IMCD exposed to elevated tonicity. Employing microarray analysis of gene expression, real-time PCR and immunoassays, we scrutinized pathways contributing to this effect.
Results:
We show that in IMCD cells CsA but not FK506 increases apoptosis upon an increase in tonicity. This effect is independent of cellular TonEBP localization or activity and reactive oxygen species. Microarray studies revealed marked quantitative differences in gene expression. Functional analysis showed overrepresentation of genes associated with cell death in presence of CsA. This correlated with increased mRNA expression of genes associated with the death receptor pathway and detection of TNFα in culture medium of cells treated with CsA.
Conclusion:
Our results show that CsA cytotoxicity is induced under elevated ambient osmolality and that death receptor signaling probably contributes to CsA cytotoxicity.
Insights
Cyclosporin-A (CsA) increases kidney cell death under high salt conditions, independent of TonEBP. This CsA toxicity involves death receptor signaling, highlighting a specific mechanism of drug-induced nephrotoxicity.
Area of Science:
- Nephrology
- Cell Biology
- Pharmacology
Background:
- Renal inner medullary collecting duct (IMCD) cells adapt to varying tonicity by regulating gene expression via Tonicity Enhancer Binding Protein (TonEBP).
- Cyclosporin-A (CsA) is suspected to interfere with TonEBP, potentially causing nephrotoxicity.
- Understanding CsA's effects on IMCD cells under osmotic stress is crucial.
Purpose of the Study:
- To investigate the cytotoxic effects of CsA on IMCD cells during elevated ambient osmolality.
- To elucidate the molecular pathways involved in CsA-induced nephrotoxicity under hypertonic conditions.
Main Methods:
- Examined CsA cytotoxicity in IMCD cells exposed to increased tonicity.
- Utilized microarray analysis, real-time PCR, and immunoassays to scrutinize contributing pathways.
- Assessed TonEBP localization, activity, and reactive oxygen species.
Main Results:
- CsA, unlike FK506, significantly increased apoptosis in IMCD cells under elevated tonicity.
- This CsA-induced apoptosis was independent of TonEBP activity and reactive oxygen species.
- Microarray analysis revealed distinct gene expression changes, with overrepresentation of cell death-associated genes, including those in the death receptor pathway and TNFα.
Conclusions:
- CsA cytotoxicity is exacerbated under elevated osmolality in IMCD cells.
- Death receptor signaling pathways likely play a significant role in CsA-induced cytotoxicity under these conditions.
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