miR-132-3p promotes the cisplatin-induced apoptosis and inflammatory response of renal tubular epithelial cells by targeting SIRT1 via the NF-KB pathway
miR-132-3p promotes the cisplatin-induced apoptosis and inflammatory response of renal tubular epithelial cells by targeting SIRT1 via the NF-KB pathway
复制标题
miR-132-3p通过NF-KB通路靶向SIRT1促进顺铂诱导的肾小管上皮细胞凋亡和炎症反应
DOI：
10.1016/j.intimp.2021.108022
复制
发表时间：
2021-07-30
影响因子：
5.6
通讯作者：
Cheng, Fan
中科院分区：
文献类型：
--
作者：
Han, Shangting;Lin, Fangyou;Cheng, Fan
顺铂是临床治疗实体瘤的一种高效、广谱的抗癌药物。然而，它会导致癌症患者的急性肾脏损伤(AKI)。因此，它的临床应用受到了限制。微小RNA(MiRNA)与AKI的发生、发展和预后密切相关，需要作为生物标志物加以验证，尤其是在顺铂诱导的AKI的早期阶段。MiRNA的一个例子是miR-132-3p，它在多种疾病的炎症反应、细胞增殖和凋亡中发挥重要作用。然而，在顺铂诱导的AKI中，其表达的差异、可能的机制和下游靶点仍不清楚。本研究旨在探讨miR-132-3p在顺铂诱导急性心肌梗死中的作用。测序和qRT-PCR显示miR-132-3p在顺铂诱导的小鼠和人近端肾小管上皮细胞(HK-2)AKI模型中显著上调。抑制顺铂刺激的HK-2细胞中miR-132-3p的表达可显著抑制细胞的凋亡和炎症反应，这种抑制作用可被miR-132-3p模拟物阻断。生物信息学和双荧光素酶报告基因分析表明，SIRT1mRNA的3‘-UTR区是miR-132-3p的直接靶点。RNAFISH和免疫荧光共定位显示miR-132-3p和SIRT1在HK-2细胞胞浆内直接结合和相互作用。在机制上，miR-132-3p上调抑制了SIRT1的表达，激活了NF-KB信号通路。相反，抑制miR-132-3p后，SIRT1的表达上调。P-p65/p65和p-IKBα/IKBα比值显著降低，顺铂诱导的炎症标志物和细胞凋亡蛋白表达水平明显降低。我们的结果提示miR-132-3p通过负性调节SIRT1和激活NF-KB信号通路而加重顺铂诱导的AKI。因此，靶向miR-132-3p可能是改善顺铂患者AKI的一种潜在的辅助治疗。
Cisplatin is a highly effective and broad-spectrum anticancer drug for the clinical treatment of solid tumors. However, it causes acute kidney injury (AKI) in patients with cancer. Consequently, its clinical application is limited. The occurrence, development, and prognosis of AKI are closely associated with microRNA (miRNA), which needs validation as a biomarker, especially for the early stages of cisplatin-induced AKI. An example of miRNA is miR-132-3p, which plays important roles in inflammatory responses, cell proliferation, and apoptosis in a variety of diseases. However, variations in its expression, potential mechanisms, and downstream targets in cisplatin-induced AKI remain unclear. This study aimed to investigate the functions of miR-132-3p in cisplatininduced AKI. Sequencing and qRT-PCR revealed that miR-132-3p was significantly upregulated in cisplatininduced AKI models of mouse and human proximal renal tubular epithelial (HK-2) cells. Apoptosis and inflammatory responses were significantly suppressed by the inhibition of the miR-132-3p expression in cisplatin-stimulated HK-2 cells, and this suppression was blocked by miR-132-3p mimics. Bioinformatics and dual luciferase reporter gene assay identified the 3 '- UTR of SIRT1 mRNA as a direct target of miR-132-3p. RNAFISH and immunofluorescence co-localization demonstrated that miR-132-3p and SIRT1 directly combined and interacted in the cytoplasm of HK-2 cells. Mechanistically, the SIRT1 expression was suppressed and the NF-KB signaling pathway was activated by the upregulation of miR-132-3p in cisplatin-induced AKI. By contrast, the SIRT1 expression was upregulated after the inhibition of miR-132-3p. The ratios of p-p65/p65 and p-IKB alpha/IKB alpha were significantly reduced, and the expression levels of inflammatory biomarkers and apoptotic proteins induced by cisplatin were obviously attenuated. Our results suggested that miR-132-3p exacerbated cisplatin-induced AKI by negatively regulating SIRT1 and activating the NF-KB signaling pathway. Therefore, targeting miR-132-3p might be a potential adjuvant therapy for ameliorating AKI in cisplatin-treated patients.