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Macrophages contribute to fibrogenesis by secreting various pro\u2010fibrogenic mediators. However, whether the sympathetic nervous system regulates renal fibrosis by modulating macrophage\u2010fibroblast interaction remains unclear. Here, it is demonstrated that norepinephrine (NE)\u2010treated macrophages promoted renal fibroblast activation through the transfer of Notch2 intracellular domain (N2ICD)\u2010enriched extracellular vesicles (EVs)\u00a0to fibroblasts. Depletion of macrophage mitigated kidney fibrosis in mice subjected to unilateral nephrectomy plus contralateral ischemia\u2010reperfusion injury (Npx\u2010IRI) or repeated low\u2010dose cisplatin (RLDC) regimen. Macrophage\u2010specific deletion of Notch2 or \u03b12B\u2010adrenoceptor disrupted N2ICD\u2010EV formation and protected mice from kidney fibrosis. Mechanistically, N2ICD stabilized Smad3 by preventing its ubiquitin\u2010dependent degradation, thereby enhancing TGF\u2010\u03b2 signaling to promote fibroblast activation. These findings establish a sympathetic nerve\u2010macrophage\u2010fibroblast axis in renal fibrosis and highlight macrophage\u2010specific Notch2 inhibition as a potential therapeutic strategy.<\/jats:p>","DOI":"10.1002\/advs.202504607","type":"journal-article","created":{"date-parts":[[2025,9,5]],"date-time":"2025-09-05T04:22:06Z","timestamp":1757046126000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Sympathetic Activation Promotes Kidney Fibrosis in Mice via Macrophage\u2010Derived N2ICD\u2010Enriched Extracellular Vesicles"],"prefix":"10.1002","volume":"12","author":[{"given":"Huiwen","family":"Ren","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Tianjin Key Laboratory of Inflammatory Biology, Center for Cardiovascular Diseases, Haihe Laboratory of Cell Ecosystem, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co\u2010sponsored 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