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首页> 外文期刊>Cellular Physiology and Biochemistry >Cyclosporin-A induced toxicity in rat renal collecting duct cells: Interference with enhanced hypertonicity induced apoptosis
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Cyclosporin-A induced toxicity in rat renal collecting duct cells: Interference with enhanced hypertonicity induced apoptosis

机译：环孢菌素A诱导的大鼠肾集合管细胞毒性：干扰高渗性引起的细胞凋亡

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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.
机译：背景/目的：大鼠肾脏内髓样集合管（IMCD）细胞在生理上暴露于广泛的环境张力。为了在渗透压变化时保持其功能，IMCD细胞诱导渗透保护和抗凋亡基因的表达，主要由转录因子张力增强结合蛋白（TonEBP）介导。讨论了某些药物，例如环孢菌素A（CsA）干扰TonEBP的活性，从而介导其肾毒性作用。我们研究的目的是进一步了解环境渗透压升高期间的CsA毒性。方法：首先，我们检查了强张性IMCD中CsA的细胞毒性。利用基因表达的微阵列分析，实时PCR和免疫测定，我们研究了促成这种作用的途径。结果：我们显示在IMCD细胞中，CsA而不是FK506在张力增加时增加凋亡。这种作用与细胞的TonEBP定位或活性以及活性氧种类无关。基因芯片研究显示基因表达存在明显的定量差异。功能分析显示在存在CsA的情况下与细胞死亡相关的基因的过度表达。这与死亡受体途径相关基因的mRNA表达增加以及在用CsA处理过的细胞的培养基中检测TNFα有关。结论：我们的研究结果表明，在高渗透压下可诱导CsA细胞毒性，而死亡受体信号传导可能会导致CsA细胞毒性。

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