Evaluation of the nephrotoxic effect of vancomycin-cisplatin andnephroprotective effect of teneligliptin In Vitro

Drug-induced nephrotoxicity is a significant clinical problem that limits the effective use of many medications, leading to increased morbidity and mortality. Vancomycin and cisplatin are well-known drugs with nephrotoxic side effects and are commonly used in clinical practice. Teneligliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor used as an oral antidiabetic agent in patients with type 2 diabetes mellitus. Recent studies suggest that teneligliptin may have a protective effect against nephrotoxicity, especially in patients undergoing cisplatin treatment. In this study, our goal was to induce nephrotoxicity related to vancomycin and cisplatin in human renal proximal tubule cell series, both in 2D and 3D culture environments. We aimed to identify potential mechanisms underlying toxicity through transcriptome analysis and demonstrate the therapeutic effect of teneligliptin on nephrotoxicity. HK-2 (human renal proximal tubule cells) cell series were cultured in 2D and 3D environments. Six groups were formed based on the administration of drugs: vancomycin, cisplatin, teneligliptin, vancomycin + teneligliptin, cisplatin + teneligliptin, and a control group. Analyses were conducted on cell survival, ROS/RNS levels (reactive oxygen and nitrogen species), apoptosis, and transcriptome. Following the application of cisplatin and vancomycin to HK-2 cells, cell viability decreased. However, when teneligliptin was added to the groups treated with cisplatin and vancomycin, an increase in cell viability was observed. In the group treated with vancomycin, the ROS level increased by 7.7 times, the RNS level increased by 8.3 times compared to the control group. In the group treated with cisplatin, the ROS level increased by 7 times, and the RNS level increased by 6 times compared to the control group. The addition of teneligliptin to the environment was found to result in an approximately 50% reduction in the increase of ROS/RNS levels. Apoptosis induced by vancomycin and cisplatin was found to be less in the groups where teneligliptin was added. As a result of transcriptome analysis, it was determined that seven genes could potentially be effective in mechanisms. In the cell series where nephrotoxicity was induced with cisplatin, the gene expressions of ARG2, GADD45G, and SOD2 decreased, while the gene expressions of UBD and PTX3 increased. In the cell series where nephrotoxicity was induced with vancomycin, the gene expressions of ARG2, NCKAP1L, PTX3, and SOD2 decreased, while the gene expressions of IGHA1 and UBD increased. It was observed that teneligliptin reduced the increased expressions of PTX3, UBD, and GADD45G associated with cisplatin toxicity, increased SOD2 expression. Additionally, teneligliptin was found to decrease IGHA1 expression in vancomycin-induced nephrotoxicity and increase NCKAP1L gene expression. The results of this study indicated that the nephrotoxic effect of cisplatin is more pronounced compared to vancomycin, and the nephrotoxic effect of cisplatin develops through various mechanisms. Additionally, it was found that teneligliptin not only exhibits anti-oxidant and anti-apoptotic effects but also possesses anti-inflammatory effects. Keywords: Vancomycin, Teneligliptin, Cisplatin, Nephrotoxicity, ARG2, GADD45G, IGHA1, NCKAP1L, PTX3, SOD2, UBD