TNF-¦Á-mediated NF-¦ÊB survival signaling impairment by cisplatin enhances JNK activation allowing synergistic apoptosis of renal proximal tubular cells
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- 作者：Giulia Benedetti ; Lisa Fredriksson ; Bram Herpers ; John Meerman ; Bob van de Water ; b.water@lacdr.leidenuniv.nl ; benedettigoe@gmail.com ; Marjo de Graauw
- 关键词：Nephrotoxicity ; Cisplatin ; TNF-¦Á ; NF-¦ÊB ; JNK
- 刊名：Biochemical Pharmacology
- 出版年：2013
- 出版时间：15 January, 2013
- 年：2013
- 卷：85
- 期：2
- 页码：274-286
- 全文大小：1942 K
文摘
Cisplatin-induced nephrotoxicity is an important limiting factor for cisplatin use. Tumor necrosis factor-¦Á (TNF-¦Á) is known to contribute to cisplatin-induced nephrotoxicity by inducing an inflammatory process aggravating the primary injury, thereby resulting in acute kidney injury (AKI). The present study investigates the pathways synergistically activated by cisplatin and TNF-¦Á responsible for TNF-¦Á-enhanced cisplatin-induced renal cell injury. To do so, immortalized renal proximal tubular epithelial cells (IM-PTECs) were co-treated with TNF-¦Á and cisplatin. Under these conditions, cisplatin induced dose-dependent apoptosis in IM-PTECs, which was significantly enhanced by TNF-¦Á. Transcriptomic analysis revealed that cisplatin inhibited the typical TNF-¦Á response and cisplatin/TNF-¦Á treatment up-regulated cell death pathways while it down-regulated survival pathways compared to cisplatin alone. In concordance, the gene expression levels of kidney injury markers combined with activation of specific inflammatory mediators were enhanced by cisplatin/TNF-¦Á treatment, resembling the in vivo cisplatin-induced nephrotoxicity response. Furthermore, combined cisplatin/TNF-¦Á treatment inhibited NF-¦ÊB nuclear translocation and NF-¦ÊB-mediated gene transcription leading to enhanced and prolonged JNK and c-Jun phosphorylation. JNK sustained activation further inhibited NF-¦ÊB signaling via a feedback loop mechanism. This led to an alteration in the transcription of the NF-¦ÊB-induced anti-apoptotic genes c-IAP2, Bcl-XL, Bruce and Bcl2 and pro-apoptotic genes Bfk and Xaf1 and consequently to sensitization of the IM-PTECs toward cisplatin/TNF-¦Á-induced toxicity. In conclusion, our findings support a model whereby renal cells exposed to both cisplatin and TNF-¦Á switch into a more pro-apoptotic and inflammatory program by altering their NF-¦ÊB/JNK/c-Jun balance.