TNF-α-mediated NF-κB survival signaling impairment by cisplatiri enhances JNK activation allowing synergistic apoptosis of renal proximal tubular cells

Cisplatin-induced nephrotoxicity is an important limiting factor for cisplatin use. Tumor necrosis factor-alpha (TNF-alpha) 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-alpha responsible for TNF-alpha-enhanced cisplatin-induced renal cell injury. To do so, immortalized renal proximal tubular epithelial cells (IM-PTECs) were co-treated with TNF-alpha and cisplatin. Under these conditions, cisplatin induced dose-dependent apoptosis in IM-PTECs, which was significantly enhanced by TNF-alpha. Transcriptomic analysis revealed that cisplatin inhibited the typical TNF-alpha response and cisplatin/TNF-alpha 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-alpha treatment, resembling the in vivo cisplatin-induced nephrotoxicity response. Furthermore, combined cisplatin/TNF-alpha treatment inhibited NF-kappa B nuclear translocation and NF-kappa B-mediated gene transcription leading to enhanced and prolonged JNK and c-Jun phosphorylation. JNK sustained activation further inhibited NF-kappa B signaling via a feedback loop mechanism. This led to an alteration in the transcription of the NF-kappa B-induced anti-apoptotic genes c-IAP2, Bcl-XL, Bruce and Bc12 and pro-apoptotic genes Bfk and Xaf1 and consequently to sensitization of the IM-PTECs toward cisplatin/TNF-alpha-induced toxicity. In conclusion, our findings support a model whereby renal cells exposed to both cisplatin and TNF-alpha switch into a more pro-apoptotic and inflammatory program by altering their NF-kappa B/JNK/c-Jun balance. (C) 2012 Elsevier Inc. All rights reserved.