细胞外囊泡包裹的miRNA介导单核细胞-内皮细胞交互作用加重糖尿病肾病肾损伤

Abstract

BACKGROUND Diabetic kidney disease (DKD) is a major microvascular complication of diabetes, with microcirculatory dysfunction and immune injury as its core pathological features. Extracellular vesicles (EVs) act as key mediators of intercellular communication, but it remains unclear whether EV-encapsulated microRNAs (miRNAs) are involved in the crosstalk between endothelial cells (ECs) and monocytes in DKD. METHODS EVs were isolated from monocytes and ECs under normal-glucose and high-glucose conditions. After characterization of EVs, differentially expressed miRNAs were screened. RNase/Triton functional assays, dual-luciferase reporter assays, gain- and loss-of-function experiments, and rescue experiments were further performed to validate the regulatory mechanisms associated with EV-miRNAs in vivo and in vitro. RESULTS Under high-glucose conditions, monocyte-derived EVs aggravated EC injury by upregulating miR-191-3p, which targets CYLD and thereby activates the NF-κB pathway. Meanwhile, EC-derived EVs enhanced monocyte inflammation and adhesion by downregulating miR-615-3p, upregulating IFNGR2, and activating the STAT3 pathway. Targeted intervention of these key molecules effectively ameliorated cellular injury in vitro and partially relieved renal damage in vivo. CONCLUSIONS This study confirms that EV-miRNA-mediated EC-monocyte crosstalk is involved in the pathogenesis of DKD, and establishes two core regulatory axes: miR-191-3p/CYLD/NF-κB and miR-615-3p/IFNGR2/STAT3. It also reveals an intrinsic link between microcirculatory dysfunction and immune injury in DKD, while the potential of these miRNAs as diagnostic biomarkers and therapeutic targets still remains to be further validated.