Sympathetic Activation Promotes Kidney Fibrosis in Mice via Macrophage-Derived N2ICD-Enriched Extracellular Vesicles

Persistent overactivation of the renal sympathetic nervous system drives kidney inflammation and fibrosis. Macrophages contribute to fibrogenesis by secreting various pro-fibrogenic mediators. However, whether the sympathetic nervous system regulates renal fibrosis by modulating macrophage-fibroblast interaction remains unclear. Here, it is demonstrated that norepinephrine (NE)-treated macrophages promoted renal fibroblast activation through the transfer of Notch2 intracellular domain (N2ICD)-enriched extracellular vesicles (EVs) to fibroblasts. Depletion of macrophage mitigated kidney fibrosis in mice subjected to unilateral nephrectomy plus contralateral ischemia-reperfusion injury (Npx-IRI) or repeated low-dose cisplatin (RLDC) regimen. Macrophage-specific deletion of Notch2 or α2B-adrenoceptor disrupted N2ICD-EV formation and protected mice from kidney fibrosis. Mechanistically, N2ICD stabilized Smad3 by preventing its ubiquitin-dependent degradation, thereby enhancing TGF-β signaling to promote fibroblast activation. These findings establish a sympathetic nerve-macrophage-fibroblast axis in renal fibrosis and highlight macrophage-specific Notch2 inhibition as a potential therapeutic strategy.