Abstract
Diabetic nephropathy (DN) is a major complication of diabetes and is responsible for 45% of all end-stage renal disease cases. Extracellular vesicles (EV) are small cell-derived vesicles that are involved in intercellular communication. MV characteristics, including cellular origin, number, composition and function, are altered in type 2 diabetes (T2DM). EV and microRNA (miRNA) in EV influence vascular disease progression by modulating inflammation and by promoting thrombus formation. In this study we aimed to characterize the cellular origin and miRNA of EVs in plasma samples of T2DM patients during various stages of DN. 96 T2DM patients were divided in three groups based on 24h urinary albumin levels; normoalbuminuria (<30mg/day), microalbuminuria (30-300mg/day), and macroalbuminuria (>300mg/day). EV were measured in plasma and were detected with the viability dye Calcein Violet and cell specific markers by flow cytometry. EV miRNA content was investigated using microRNA profiling qPCR array (752 miRNAs). Seven differentially expressed miRNAs were validated by qPCR. In microalbuminuria patients, total numbers of EV, and EV from endothelial cells, leukocytes and erythrocytes were significantly elevated. In macroalbuminuria patients, total EV numbers and EV derived from platelets, leukocytes, granulocytes and erythrocytes were elevated compared to diabetic controls. Profiling of the miRNAs in the EV revealed seven differentially expressed miRNAs. Validation of these miRNAs showed significantly increased EV expression of miR-99a-5p in macroalbuminuria patients compared to normoalbuminuria and microalbuminuria patients. Elevated levels of miR-99a-5p in EV may contribute to renal inflammation and fibrosis, as miR-99a-5p targets fibroblast growth factor receptor 3 and mammalian target of rapamycin. EV from T2DM patients with microalbuminuria and macroalbuminuria display pro-inflammatory and pro-coagulant profiles. Further research is needed to explore the role of EV and EV mediated miR-99a-5p delivery in diabetic renal injury.
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