Taguchi Hiroki, Sumi Daigo, Uemura Ayumi, Matsumoto Kanako, Fujishiro Hitomi
Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima 770-8514, Japan.
Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima 770-8514, Japan.
Toxicol Appl Pharmacol. 2025 Jan;494:117171. doi: 10.1016/j.taap.2024.117171. Epub 2024 Nov 24.
Anti-cancer drug cisplatin (CDDP) causes severe acute kidney injury (AKI). CDDP-induced AKI does not occur immediately after administration, but rather 6 to 10 days after administration. However, the mechanism underling the delayed renal injury by CDDP is not well understood. In a previous investigation using immortalized cells derived from the S1, S2, and S3 segments of the proximal tubules, we found that S3 cells were more sensitive to CDDP than S1 and S2 cells. In this study, we examined whether S1, S2, and S3 cells would be useful in elucidating the mechanism of CDDP-induced delayed renal injury and whether the high sensitivity of S3 cells contributes to CDDP-induced delayed renal injury. Measurement of platinum (Pt) content by ICP-MS showed that Pt accumulation peaked at 15 min after CDDP exposure in each cell type. Even when the medium was replaced with CDDP-free medium after the 15-min CDDP exposure and the cells were further incubated, delayed cytotoxicity was still observed. The S3 cells exhibited greater sensitivity to CCDP than the S1 and S2 cells at all time points after the medium change. To investigate the mechanism of the CDDP-induced delayed cytotoxicity, we examined the cell cycle distribution of cells after CDDP exposure. The results showed that CDDP-induced perturbation of cell cycle was greater in S3 than in S1 and S2 cells. These results suggest that perturbation of the cell cycle in S3 cells due to enhanced CDDP-DNA adduct formation contributes to the high susceptibility of S3 cells to CDDP-induced delayed cytotoxicity.
抗癌药物顺铂（CDDP）会导致严重的急性肾损伤（AKI）。顺铂诱导的急性肾损伤并非在给药后立即发生，而是在给药后6至10天出现。然而，顺铂导致延迟性肾损伤的机制尚未完全明确。在先前一项使用源自近端小管S1、S2和S3节段的永生化细胞进行的研究中，我们发现S3细胞比S1和S2细胞对顺铂更敏感。在本研究中，我们探究了S1、S2和S3细胞是否有助于阐明顺铂诱导的延迟性肾损伤机制，以及S3细胞的高敏感性是否导致了顺铂诱导的延迟性肾损伤。通过电感耦合等离子体质谱法（ICP-MS）测量铂（Pt）含量显示，每种细胞类型在暴露于顺铂后15分钟时铂积累达到峰值。即使在15分钟的顺铂暴露后将培养基更换为不含顺铂的培养基并对细胞进行进一步孵育，仍观察到延迟性细胞毒性。在更换培养基后的所有时间点，S3细胞对顺铂的敏感性均高于S1和S2细胞。为了研究顺铂诱导的延迟性细胞毒性机制，我们检测了顺铂暴露后细胞的细胞周期分布。结果显示，顺铂诱导的细胞周期紊乱在S3细胞中比在S1和S2细胞中更明显。这些结果表明，由于顺铂-DNA加合物形成增加导致S3细胞中的细胞周期紊乱，这有助于S3细胞对顺铂诱导的延迟性细胞毒性具有高敏感性。
