Institute of Nephrology, Zhongda Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, China.
Cell Biochem Funct. 2020 Jun;38(4):384-391. doi: 10.1002/cbf.3474. Epub 2019 Dec 30.
Acute kidney injury (AKI) is a common adverse reaction of the anticancer drug. Among these chemotherapeutic agents, cisplatin, an effective chemotherapeutic drug, is extensively applied to the treatment of solid tumours, yet various adverse reactions, especially AKI, often limit their use. However, the pathogenesis of AKI caused by cisplatin remains poorly clarified. Therefore, we tested whether microRNAs, which have been certified as key regulators of disease are involved in this process. AKI mouse and HK2 cells were treated with cisplatin. Annexin V/PI staining and cleaved caspase-3 were used to assess apoptosis. Western blot analyses and qRT-PCR were used to evaluate the protein and mRNA level of TRPC6 and DRP1. miR-26a was remarkably decreased in cisplatin-induced AKI and in cisplatin co-cultured HK2 cells. Furthermore, we used a miR-26a mimics in vitro and found that apoptosis was alleviated than that in the control cells. We further verified that miR-26a protected against cisplatin-induced cell apoptosis by acting on transient receptor potential channel 6 (TRPC6) which can regulate the expression of dynamin-related protein 1 (DRP1), thus inhibited the mitochondrial apoptosis pathway. Therefore, the study unveiled that miR-26a/TRPC6/DRP1 is a novel protective pathway in cisplatin-induced AKI and may be targeted for the prevention and treatment of drug-related renal injury. SIGNIFICANCE OF THE STUDY: Our study found that miR-26a was significantly downregulated during cisplatin-induced AKI and during cisplatin co-cultured HK2 cells. Further, in vitro we used miR-26a mimic to intervene cells and found that apoptosis alleviated compared with control group. We further verified that miR-26a protected cisplatin-induced apoptosis by target transient receptor potential channel 6 (TRPC6) which can regulate the expression of dynamic-related protein 1 (DRP1) and inhibit the mitochondrial apoptosis pathway. Thus, miR-26a/TRPC6/DRP1 is a new protective pathway in cisplatin-induced AKI and may be targeted for the prevention and treatment of drug-related acute kidney injury.
急性肾损伤（AKI）是抗癌药物的常见不良反应。在这些化疗药物中，顺铂是一种有效的化疗药物，广泛应用于实体瘤的治疗，但各种不良反应，尤其是 AKI，常限制其应用。然而，顺铂引起 AKI 的发病机制仍不清楚。因此，我们检测了 microRNAs 是否参与了这一过程，microRNAs 已被证实是疾病的关键调节因子。用顺铂处理 AKI 小鼠和 HK2 细胞，用 Annexin V/PI 染色和 cleaved caspase-3 评估细胞凋亡，用 Western blot 分析和 qRT-PCR 评估 TRPC6 和 DRP1 的蛋白和 mRNA 水平。顺铂诱导的 AKI 小鼠和顺铂共培养的 HK2 细胞中 miR-26a 显著降低。此外，我们在体外使用 miR-26a 模拟物，发现细胞凋亡较对照组减轻。我们进一步验证了 miR-26a 通过作用于瞬时受体电位通道 6（TRPC6）来保护顺铂诱导的细胞凋亡，TRPC6 可以调节 dynamin-related protein 1（DRP1）的表达，从而抑制线粒体凋亡途径。因此，该研究揭示了 miR-26a/TRPC6/DRP1 是顺铂诱导 AKI 的一种新的保护途径，可能成为预防和治疗药物相关肾损伤的靶点。
本研究发现，顺铂诱导 AKI 及顺铂共培养 HK2 细胞中 miR-26a 显著下调。进一步，我们在体外使用 miR-26a 模拟物干预细胞，发现与对照组相比细胞凋亡减轻。我们进一步验证了 miR-26a 通过靶向瞬时受体电位通道 6（TRPC6）来保护顺铂诱导的凋亡，TRPC6 可以调节 dynamin-related protein 1（DRP1）的表达并抑制线粒体凋亡途径。因此，miR-26a/TRPC6/DRP1 是顺铂诱导 AKI 的新的保护途径，可能成为预防和治疗药物相关急性肾损伤的靶点。
