Key result
Extracellular vesicles derived from adipose mesenchymal stem cells transferred miR-26a-5p to target TLR4, inactivating the NF-κB/VEGFA pathway and protecting against diabetic nephropathy in mice.
Why the study?
Diabetic nephropathy is an increasing complication of diabetes in China, and extracellular vesicles carrying microRNAs may offer a novel therapeutic approach.
Does treatment with ADSC-derived EVs containing miR-26a-5p improve diabetic nephropathy in preclinical models?
Does treatment with ADSC-derived EVs containing miR-26a-5p improve diabetic nephropathy in preclinical models?
ADSC-derived EVs containing miR-26a-5p protect against diabetic nephropathy by targeting TLR4 and downregulating the NF-κB/VEGFA signaling pathway in preclinical models.
May inform EV-based therapies for diabetic nephropathy; leaves open translation from murine models.
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.
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Duan et al. (2020) studied Diabetic nephropathy (n=24). Adipose mesenchymal stem cell-derived extracellular vesicles containing microRNA-26a-5p vs. PBS / control mice was evaluated on Pathological symptoms of diabetic nephropathy (urine protein, serum creatinine, blood urea nitrogen, and podocyte apoptosis). Extracellular vesicles derived from adipose mesenchymal stem cells transferred miR-26a-5p to target TLR4, inactivating the NF-κB/VEGFA pathway and protecting against diabetic nephropathy in mice.
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