promotes cisplatin-induced nephrotoxicity through inflammation mediated by the MAPK/NF-κB signaling pathway.

Background: The nephrotoxicity induced by cisplatin (DDP) has been a severe obstacle for its clinical use in anticancer treatment. The apoptosis and inflammation induced by DDP are the main causes of the nephrotoxicity. Transient receptor potential ankyrin 1 () is a non-selective cation ligand-gated channel that is involved in the inflammation progress.

Methods: The apoptosis, inflammation, MAPK/NF-κB signaling pathway, and expression were assessed after HEK293 cells had been induced by DDP, and the role of in apoptosis and inflammation of DDP-induced HEK293 cells treated with antagonist HC-030031 was also evaluated by quantitative reverse transcription-polymerase chain reaction (qRT-PCR), flow cytometry, and western blot assays.

Results: The cell viability was reduced by DDP in both a time-dependent and dose-dependent manner with a minimal cytotoxic concentration of 10 μM. Moreover, DDP induced an enhancement of the apoptosis and inflammation in a dose-dependent manner, as indicated by the increase of the relative protein level of cleaved-caspase3 (cleaved-cas3), the cleavage product of caspase-3 substrate poly-ADP-ribose polymerase (cleaved-PARP) and inducible nitric oxide synthase (iNOS), and the messenger RNA (mRNA) expression level of interleukin (), , tumor necrosis factor-α (), and interferon-γ (). Additionally, DDP treatment increased the protein phosphorylation expression of IKKβ, JNK, ERK, and p38 in a dose-dependent manner, which was antagonized by the treatment of NF-κB-specific inhibitor BAY 11-7082 and pan-MAPK inhibitor U0126. It was also found that DDP upregulated the expression of at both the mRNA and protein levels in a dose-dependent manner. Besides, block of with HC-030031 relieved the apoptosis, diminished the level of , , , and , reduced the level of cleaved-cas3, cleaved-PARP, and iNOS, decreased the p-IKKβ, p-JNK, p-ERK, and p-p38 expression, and enhanced the expression of IκBα.

Conclusions: Taken together, these results indicate that regulates DDP-induced nephrotoxicity via inflammation mediated by the MAPK/NF-κB signaling pathway in HEK293 cells.