M1
macrophage‐derived exosomes aggravate diabetic nephropathy by regulating the
WTAP
/
S1PR2
axis
Lei Li, Hongmei Liu, Yu Mao, Huanhuan Wang, Lige Song, Zhiqiang Kang ABSTRACT
Background
Diabetic nephropathy (DN) is a severe microvascular complication of diabetes mellitus. The specific role of M1 macrophage‐derived exosomes in DN progression remains largely unexplored.
Methods
THP‐1 monocytes were differentiated into M0 macrophages and polarized into M1 macrophages for exosome extraction. WTAP was silenced using shRNA to generate WTAP‐deficient exosomes. Glomerular endothelial cells (GECs) were exposed to high glucose (HG) and co‐incubated with modified exosomes. Cell viability, oxidative stress, apoptosis, barrier function, and angiogenic capacity were assessed. The WTAP‐S1PR2 interaction was validated by RIP, MeRIP, and dual‐luciferase assays. In vivo, db/db mice received tail vein injections of respective exosomes for 8 weeks, followed by assessments of renal function, histopathology, and inflammation.
Results
M1 exosomes were internalized by GECs. WTAP delivered by shNC/M1‐Exo bound S1PR2 mRNA, enhancing its m6A modification and stability, thereby activating the RhoA/ROCK1 axis and aggravating HG‐induced GEC injury, oxidative stress, apoptosis, and endothelial permeability. Conversely, shWTAP/M1‐Exo attenuated these effects, and S1PR2 overexpression reversed the protective effects. In vivo, shWTAP/M1‐Exo improved renal function, ameliorated histopathological damage and fibrosis, and reduced systemic inflammation in db/db mice.
Conclusion
M1 macrophage‐derived exosomes promote DN progression by delivering WTAP to stabilize S1PR2 mRNA in an m6A‐dependent manner. Engineered exosomes lacking WTAP represent a promising targeted nanomedicine strategy for DN treatment.