Glomerular mesangial derived extracellular vesicles deteriorate diabetic kidney disease via miR-3147/PRKAR2B axis

To investigate the clinical significance and role of miRNAs with shared patterns in both peripheral blood and kidney tissue-derived extracellular vesicles (EVs) in diabetic kidney disease (DKD). miRNA-Seq was performed on plasma EV samples from DKD and diabetes mellitus (DM) patients, and the validation, clinical significance and mechanistic exploration of the specific differentially expressed miRNAs (De-miRNAs) were evaluated in a cohort of DKD-derived plasma and glomerular mesangial biopsies and high glucose (HG)-treated mesangial cells (MCs). A total of 15 EV-derived De-miRNAs was identified by miRNA-Seq, among which miR-3147 was the most significantly differentially expressed. Elevated miR-3147 was found in DKD patients compared with DM patients and was correlated with multiple clinical parameters, especially the eGFR-MDRD and eGFR-CKD-EPI. Further in situ miR-3147 localization confirmed the elevated expression pattern in DKD-derived kidney samples, which were co-stained with the mesangial marker Thy-1.1. miR-3147 was also overexpressed in HG-treated MCs, and its overexpression promoted MC proliferation and early-stage apoptosis under HG conditions. In addition, PRKAR2B was confirmed as a target gene of miR-3147. Our results demonstrated that elevated plasma EV-derived miRNA-3147 correlated with glomerular function and DKD diagnostic value and that the overexpression of miRNA-3147 in the glomerular MCs may exacerbate DKD through the regulation of MC proliferation and apoptosis via PRKAR2B.