Transient receptor potential ankyrin 1 mediates cisplatin-induced apoptosis in renal tubular cells via calcium-dependent signaling pathway

Abstract

Background: Cisplatin has been a vital drug used for tumor treatment because of its excellent effect on numerous malignant solid cancers. Nonetheless, its nephrotoxicity is non-negligible in clinical practice. This study aims to provide a new understanding of the molecular mechanism of transient receptor potential ankyrin 1 (TRPA1) in cisplatin-induced renal apoptosis. Methods: We evaluated the effect on apoptosis, TRPA1 expression, and intracellular calcium concentration of human kidney 2 (HK-2) cells induced by diamminedichloroplatinum (DDP). Additionally, we also assessed DDP-induced apoptosis, the expression of Bax, caspase3, cleaved-cas3, p53, Bcl-2 and intracellular calcium concentration combined with HC-030031 and/or pifithrin-α. The effect of FK506 on apoptosis of HK-2 cells induced by DDP and the expression of the nuclear factor of activated T cells (NFAT) protein treated with HC-030031, pifithrin-α, and/or FK506 were also explored. Results: The results showed that apoptosis, TRPA1 expression, and intracellular calcium concentration of HK-2 cell induced by DDP were enhanced in a dose-dependent manner. HC-030031 and pifithrin-α relieved apoptosis, and intracellular calcium concentration and the expression of NFAT and phospho-NFAT (p-NFAT) were induced by DDP. HC-030031 combined with pifithrin-α further aggravated the above-mentioned tendency, including relieved apoptosis, intracellular calcium concentration, and NFAT and p-NFAT expression. HC-030031 and FK506 decelerated the apoptosis, and NFAT and p-NFAT expression of HK-2 cells was induced by DDP, while simultaneous treatment with HC-030031 and FK506 further decreased apoptosis and protein expression. However, the expression of Bcl-2 increased when HC-030031, pifithrin-α, or FK506 was used alone, and HC-030031 combined with pifithrin-α or FK506 further improved the expression of Bcl-2. Conclusions: TRPA1 mediates cisplatin-induced apoptosis in renal tubular cells via the calcineurin-nuclear factor of activated T-cells-p53 signaling pathway.