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<p>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.&#xa0;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.&#xa0;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.&#xa0;Our study shows that the siRBM15-Exo effectively suppress MSTN expression to alleviate DN progression, providing promising translational potential for DN therapy.</p> Graphical Abstract <p>SiRBM15-loaded engineered MSC exosomes (siRBM15-Exo) effectively reduce MSTN expression through m6A-dependent mechanisms, thereby attenuating DN progression by suppressing inflammation, ferroptosis, oxidative stress, and senescence.</p> <p></p>

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

  • 期刊论文

  • 发表日期：

    2025年11月17日

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  • Qianlan Dong,
  • Longhao Dong,
  • Yanting Zhu,
  • Xiaoming Wang,
  • Xiaohui Yan

摘要

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.

Graphical Abstract

SiRBM15-loaded engineered MSC exosomes (siRBM15-Exo) effectively reduce MSTN expression through m6A-dependent mechanisms, thereby attenuating DN progression by suppressing inflammation, ferroptosis, oxidative stress, and senescence.