Epigenetic silencing of MSTN via m6A modification underlies the renoprotective effects of engineered MSC exosomes with RBM15 depletion in diabetic nephropathy

Diabetic nephropathy (DN) is a leading complication of diabetes mellitus. Engineered exosomes have shown promise in disease treatment by enabling targeted cargo delivery. RNA-binding motif protein 15 (RBM15) accelerates the progression of DN. This study developed siRBM15-loaded exosomes and evaluated their therapeutic efficacy and mechanisms. Exosomes were isolated from human umbilical cord MSCs (hucMSCs) and loaded with siRBM15 (siRBM15-Exo) by electroporation. Human glomerular mesangial cells (HGMCs) were exposed to high glucose (HG). A rat model of DN was generated by streptozotocin induction. The effects on cell pathological responses were evaluated by detecting α-SMA and Collagen IV expression, TNF-α and IL-1β levels, ROS and MDA levels, SOD activity, the percentage of SA-β-gal positive cells, and senescence-associated factors p53 and p21. The impact on DN rats was assessed by measuring pathological changes and inflammation. Myostatin (MSTN) and RBM15 were overexpressed in DN kidneys and HG-stimulated HGMCs. MSTN depletion reduced the production of the related markers of fibrosis, inflammation, oxidative stress, and senescence in HG-stimulated HGMCs. Mechanistically, RBM15 stabilized MSTN mRNA via m6A methylation. Reintroducing MSTN reversed these protective effects of RBM15 silencing on HG-induced pathological responses in HGMCs. Furthermore, siRBM15-Exo attenuated HG-induced fibrotic, inflammatory, oxidative, and senescent responses in HGMCs and mitigated inflammation and pathological changes in DN rats. SiRBM15-Exo downregulated MSTN in HG-stimulated HGMCs. Our study shows that the siRBM15-Exo effectively suppress MSTN expression to alleviate DN progression, providing promising translational potential for DN therapy.