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Renal sympathetic nerve activity is elevated in patients and experimental animals with CKD and contributes to renal interstitial fibrosis in obstructive nephropathy. However, the mechanisms underlying sympathetic overactivation in renal fibrosis remain unknown. Norepinephrine (NE), the main sympathetic neurotransmitter, was found to promote TGF\u2010\u03b21\u2010induced epithelial\u2010mesenchymal transition (EMT) and fibrotic gene expression in the human renal proximal epithelial cell line HK\u20102. Using both genetic and pharmacological approaches, we identified that NE binds G\u03b1q\u2010coupled \u03b11\u2010adrenoceptor (\u03b11\u2010AR) to enhance EMT of HK\u20102 cells by activating p38\/Smad3 signaling. Inhibition of p38 diminished the NE\u2010exaggerated EMT process and increased the fibrotic gene expression in TGF\u2010\u03b21\u2010treated HK\u20102 cells. Moreover, the pharmacological blockade of \u03b11\u2010AR reduced the kidney injury and renal fibrosis in a unilateral ureteral obstruction mouse model by suppressing EMT in the kidneys. Thus, sympathetic overactivation facilitates EMT of renal epithelial cells and fibrosis via the \u03b11\u2010AR\/p38\/Smad3 signaling pathway, and \u03b11\u2010AR inhibition may be a promising approach toward treating renal fibrosis.<\/jats:p>","DOI":"10.1096\/fj.202000737rrr","type":"journal-article","created":{"date-parts":[[2020,9,17]],"date-time":"2020-09-17T01:36:38Z","timestamp":1600306598000},"page":"14892-14904","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Inhibition of \u03b11\u2010adrenoceptor reduces TGF\u2010\u03b21\u2010induced epithelial\u2010to\u2010mesenchymal transition and attenuates UUO\u2010induced renal fibrosis in mice"],"prefix":"10.1096","volume":"34","author":[{"given":"Huiwen","family":"Ren","sequence":"first","affiliation":[{"name":"Department of Pharmacology Tianjin Key Laboratory of Inflammation Biology School of Basic Medical Sciences Tianjin Medical University Tianjin 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