M1 macrophage-derived exosomes aggravate diabetic nephropathy by regulating the WTAP/S1PR2 axis.

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.