miR-132-3p promotes the cisplatin-induced apoptosis and inflammatory response of renal tubular epithelial cells by targeting SIRT1 via the NF-KB pathway

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.

Automated summary

The study showed that miR-132-3p was significantly upregulated in cisplatin-induced AKI models, exacerbating AKI by negatively regulating SIRT1 and activating the NF-κB signaling pathway. Inhibition of miR-132-3p expression effectively suppressed apoptosis and inflammatory responses in cisplatin-stimulated cells.