Abstract
Diabetic nephropathy (DN) is a complication of diabetes that is increasing in prevalence in China. Extracellular vesicles (EVs) carrying microRNAs (miRs) may represent a useful tool in the development of therapies for DN. Here, we report that EVs released by adipose-derived mesenchymal stem cells (ADSCs) during DN contain a microRNA, miR-26a-5p, that suppresses DN. Using bioinformatic analyses, we identified differentially expressed miRs in EVs from ADSCs and in DN and predicted downstream regulatory target genes. We isolated mesenchymal stem cells (MSCs) from adipose tissues and collected EVs from the ADSCs. We exposed mouse glomerular podocytes and MP5 cells to high glucose (HG), ADSC-derived EVs, miR-26a-5p inhibitor/antagomir, Toll-like receptor 4 (TLR4) plasmids, or the NF-κB pathway activator (phorbol-12-myristate-13-acetate, or PMA). We used the cell counting kit-8 (CCK-8) assay and flow cytometry to investigate the impact of miR-26a-5p on cell viability and apoptosis and validated the results of these assays with in vivo experiments in nude mice. We found that in DN, miR-26a-5p is expressed at very low levels, whereas TLR4 is highly expressed. Of note, EVs from ADSCs ameliorated the pathological symptoms of DN in diabetic mice and transferred miR-26a-5p to HG-induced MP5 cells, improving viability while suppressing the apoptosis of MP5 cells. We also found that miR-26a-5p protects HG-induced MP5 cells from injury by targeting TLR4, inactivating the NF-κB pathway, and downregulating vascular endothelial growth factor A (VEGFA). Moreover, ADSC-derived EVs transferred miR-26a-5p to mouse glomerular podocytes, which ameliorated DN pathology. These findings suggest that miR-26a-5p from ADSC-derived EVs protects against DN.
Highlights
Diabetic nephropathy (DN), a common microvascular complication of diabetes, is one of the major causes of death among patients with diabetes [1]
These results suggest that miR26a-5p delivered by adipose-derived mesenchymal stem cells (ADSCs)-derived extracellular vesicles (EVs) protect against DN by regulating Toll-like receptor 4 (TLR4)
Because EVs have been shown to confer protection against renal diseases [27], we studied the effects of miR-26a-5p delivery by EVs derived from ADSCs on the pathological symptoms of DN
Summary
Diabetic nephropathy (DN), a common microvascular complication of diabetes, is one of the major causes of death among patients with diabetes [1]. Evidence suggests that extracellular vesicles (EVs) slow the development of DN by protecting podocytes from injury [9]. Elucidating mechanisms by which EVs regulate podocyte injury may represent a therapeutic target for the treatment of DN. The NF-kB pathway could promote the expression of vascular endothelial growth factor A (VEGFA) [23], which contributes to glomerular endothelial cell dysfunction as well as albuminuria in DN [24]. Taking these findings into consideration, we hypothesized that ADSC-derived EVs transferred miR-26a5p to other cells regulating the progression of DN by targeting TLR4 and modulating NF-kB and VEGFA. This study may help to identify a novel strategy for the control of DN
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