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However, the underlying mechanisms remain unclear. This study aims to delineate the spatiotemporal contribution of adrenergic signalling in diabetic kidney fibrosis to reveal potential therapeutic targets.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>A model of diabetic nephropathy was induced by in db\/db mice. Gene expression in kidneys was profiled by RNA\u2010seq analyses, western blot and immunostaining. Subcellular\u2010localized fluorescence resonance energy transfer (FRET) biosensors determined adrenergic signalling microdomains in MCs. Effects of oral rolipram, a phosphodiesterase 4 (PDE4) inhibitor, on the model were measured.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Our model exhibited impaired kidney function with elevated expression of adrenergic and fibrotic genes, including <jats:italic>Adrb1, PDEs, Acta2<\/jats:italic> and <jats:italic>Tgf\u03b2<\/jats:italic>. RNA\u2010seq analysis revealed that MCs with dysregulated YAP pathway were crucial to the extracellular matrix secretion in kidneys from diabetic nephropathy patients. In cultured MCs, TGF\u2010<jats:italic>\u03b2<\/jats:italic> promoted profibrotic gene transcription, which was regulated by nuclear\u2010localized <jats:italic>\u03b2<\/jats:italic>\u2010adrenoceptor signalling. Mechanistically, TGF\u2010<jats:italic>\u03b2<\/jats:italic> treatment diminished nuclear\u2010specific cAMP signalling in MCs and reduced PKA\u2010dependent phosphorylation of YAP, leading to its activation. In parallel, db\/db mouse kidneys showed increased expressions of PDE4B and PDE4D. Treatment with oral rolipram alleviated kidney fibrosis in db\/db mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>Diabetic nephropathy impaired nuclear\u2010localized <jats:italic>\u03b2<\/jats:italic><jats:sub>1<\/jats:sub>\u2010adrenoceptor\u2010cAMP signalling microdomain through upregulating PDE4 expression, promoting fibrosis in MCs via PKA dephosphorylation\u2010dependent YAP activation. Our results suggest PDE4 inhibition as a promising strategy for alleviating kidney fibrosis in diabetic nephropathy.<\/jats:p><\/jats:sec><jats:sec><jats:title>LINKED ARTICLES<\/jats:title><jats:p>This article is part of a themed issue Drugs and Drug Targets in Metabolic and Chronic Inflammatory Diseases. To view the other articles in this section visit <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/bph.v182.20\/issuetoc\">http:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/bph.v182.20\/issuetoc<\/jats:ext-link><\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.17347","type":"journal-article","created":{"date-parts":[[2024,10,3]],"date-time":"2024-10-03T02:01:07Z","timestamp":1727920867000},"page":"4926-4943","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Diminished nuclear\u2010localized <i>\u03b2<\/i>\u2010adrenoceptor signalling activates YAP to promote kidney fibrosis in diabetic nephropathy"],"prefix":"10.1111","volume":"182","author":[{"given":"Wenjing","family":"Xiang","sequence":"first","affiliation":[{"name":"Department of Pharmacology, School of Medicine Southern University of Science and Technology  Shenzhen 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