Peripheral extracellular vesicle-derived miR-150-3p exacerbates acute kidney injury following acute pancreatitis by promoting ferroptosis through FTH1 signaling

Acute kidney injury following acute pancreatitis (AP-AKI) is one of the most fatal complications caused by acute pancreatitis (AP). Extracellular vesicles (EVs) in circulating blood are believed to be crucial to the process of AP-AKI, but the mechanisms are still unclear. In this study, we first constructed an AP-AKI rat model by retrograde sodium taurocholate through the pancreatic duct and then injected circulating blood-derived EVs into AP-AKI rats. Measurements of peripheral blood creatinine and urea nitrogen levels showed that EVs could add to kidney injury in AP-AKI rats. By analyzing the levels of renal Fe2+, cyclooxygenase 2 (COX-2), malondialdehyde (MDA), and glutathione peroxidase 4 (GPX4), we also found that extracted EVs could aggravate renal tubular ferroptosis in AP-AKI rats. Using high-throughput sequencing, we screened for high expression of EV miR-150-3P in AP-AKI patients. In vitro, we found that overexpressed miR-150-3P can influence MDA, Fe2+, lipid peroxide and GSH levels in HK-2 cells and ultimately aggravate ferroptosis. Next, through a dual-luciferase assay, we confirmed that miR-150-3p could exacerbate ferroptosis by directly targeting ferritin heavy chain 1 (FTH1). Finally, in AP-AKI rats, we again demonstrated that overexpression of miR-150-3P exacerbated renal ferroptosis through the miR-150-3P/FTH1 axis. Collectively, these findings provide new avenues to explore the mechanisms of the onset and exacerbation of AP-AKI.