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 cisplatin-induced AKI. Sequencing and qRT-PCR revealed that miR-132-3p was significantly upregulated in cisplatin-induced 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. RNA-FISH 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-κB 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-IκBα/IκBα 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-κB signaling pathway. Therefore, targeting miR-132-3p might be a potential adjuvant therapy for ameliorating AKI in cisplatin-treated patients.
Keywords: AKI; Cisplatin; Inflammation; NF-κB; SIRT1; miR-132-3p.
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