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

Abstract 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.