M2 macrophage exosomal SBF2-AS1 suppresses NLRP3-mediated pyroptosis to ameliorate high glucose-induced podocyte injury through the miR-650/MDM2/NEK7 axis.
TL;DR
M2-Exo deliver SBF2-AS1 to regulate the miR-650/MDM2/NEK7 axis, inhibit NLRP3-mediated podocyte pyroptosis, and ameliorate the progression of DN.
Abstract
Background
To investigate the protective effect of M2 macrophage-derived exosomes (M2-Exo) on high glucose-induced podocyte injury and the underlying molecular mechanism.
Methods
THP-1 cells were induced to differentiate into M2 macrophages using PMA combined with IL-4/IL-13, and exosomes were extracted and identified. A high glucose-induced podocyte injury model was established in vitro, and a streptozotocin (STZ)-induced diabetic nephropathy (DN) mouse model was established in vivo to evaluate the protective effect and mechanism of M2-Exo.
Results
M2-Exo were successfully isolated and identified. M2-Exo intervention restored podocyte viability, inhibited apoptosis, and suppressed NLRP3-mediated pyroptosis. SET-binding factor 2-antisense RNA 1 (SBF2-AS1) was highly expressed in M2-Exo and functioned as a competing endogenous RNA (ceRNA) by competitively binding to miR-650, thereby upregulating mouse double minute 2 (MDM2) expression. MDM2, acting as an E3 ubiquitin ligase, promoted NIMA-related kinase 7 (NEK7) ubiquitination and degradation, subsequently inhibiting NOD-like receptor family pyrin domain containing 3 (NLRP3) pyroptosis pathway activation. In vivo experiments confirmed that SBF2-AS1-overexpressing M2-Exo improved renal function and alleviated renal pathological injury in DN mice.
Conclusion
M2-Exo deliver SBF2-AS1 to regulate the miR-650/MDM2/NEK7 axis, inhibit NLRP3-mediated podocyte pyroptosis, and ameliorate the progression of DN.