Modulation of urinary EV-derived miR-145 and miR-126 in the progression of diabetic nephropathy

Diabetic nephropathy (DN) is a severe kidney-related complication of type 1 and type 2 diabetes and the most frequent cause of end-stage kidney disease. Currently, urinary albumin and creatinine excretion rate are used to assess the presence of DN but they have proven some limitations. Extracellular Vesicles present in the urine (uEVs) mainly derive from cells of the nephron, thus representing an interesting tool to mirror the kidney physiological state. Here, we focused the attention on the role of miR126 and miR145 contained in uEVs as markers of renal damage and renal cells impairment during DN progression. The levels of miR126 and miR145 have been evaluated in the uEVs of type 2 diabetes patients. Moreover, we set up a murine model of type 1 DN in vivo and a model of renal proximal tubular cell diabetic damage in vitro, to assess the miR expression level in renal cells and deriving EVs. We found an inverse correlation between miR126 and miR145 during DN progression, with increase of miR145 and decrease of miR126 in uEVs from diabetic patients with no albuminuria, micro and macroalbuminuria. Moreover, the analysis of miRNAs in uEVs of DN mice confirmed the results of DN patients. Finally, renal tubular cells exposed to high glucose and albumin released higher levels of EV-contained miR145. In conclusion, this work allows a deeper knowledge in the landscape of DN features, evaluating the variation of mir126 and mir145 as expression of the progression of renal diabetic damage, and proposes new EV-based urinary biomarkers.