MicroRNA-382 Is Involved in Acute Kidney Injury via Regulating STAT1 Signaling

Acute kidney injury (AKI), characterized by inflammation and oxidative stress, is a life-threatening clinical presentation. We previously demonstrated the role of miR-382 in the progression of chronic kidney disease (CKD). However, the role of miR-382 in AKI is unknown. Genetic depletion of miR-382 exacerbated renal dysfunction, histologic lesions, apoptosis of epithelial cells, and oxidative stress in kidneys in ischemia-reperfusion (I/R)- and sepsis-induced AKI. In vitro, downregulation of miR-382 accompanied with activation of phosphorylation of signal transducer and activator of transcription 1 (STAT1) were induced in mouse renal tubular epithelial cells (mTECs) with hypoxia/reoxygenation (H/R) and lipopolysaccharide (LPS) treatments. Colocalization of phosphorylated STAT1 (p-STAT1) and Lotus tetragonolobus lectin (LTL) suggested the activation of STAT1 signaling in renal epithelial after I/R injury (IRI). Overexpression of miR-382 in mTECs abrogated phosphorylation of STAT1, generation of interleukin-6 (Il-6), tumor necrosis factor-α (Tnf-α), and Il-1β as well as reactive oxygen species (ROS) and apoptosis after H/R- and LPS treatments. Additionally, loss of miR-382 was found in isolated macrophages from kidney during I/R-induced AKI. Upregulation of miR-382 in Raw264.7 cells inactivated STAT1 signaling and hindered polarization of M1 macrophages inhibiting Il-6 and inducible nitric oxide synthase (iNos). Inhibition of STAT1 pharmacologically reduced Il-1β, Il-6, and Tnf-α in Raw264.7 after H/R. Taken together, these results demonstrated the protective role of miR-382 in I/R- and sepsis-induced AKI, suggesting miR-382 as a novel therapeutic strategy for AKI.