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Connective tissue growth factor (CTGF) plays a crucial role in the pathogenesis of hepatic fibrosis and emerges as downstream of the profibrogenic cytokine transforming growth factor-<jats:italic>\u03b2<\/jats:italic>(TGF-<jats:italic>\u03b2<\/jats:italic>). We aimed to investigate the molecular events that lead from the Ang II receptor to CTGF upregulation in human hepatic stellate cells, a principal fibrogenic cell type. Ang II produced an early, AT<jats:sub>1<\/jats:sub>receptor-dependent stimulation of CTGF expression and induced a rapid activation of PKC and its downstream p38 MAPK, thereby activating a nuclear factor-<jats:italic>\u03ba<\/jats:italic>B (NF-<jats:italic>\u03ba<\/jats:italic>B) and Smad2\/3 cross-talk pathway. Chemical blockade of NF-<jats:italic>\u03ba<\/jats:italic>B and Smad2\/3 signaling synergistically diminished Ang II-mediated CTGF induction and exhibited an additive effect in abrogating the ECM accumulation caused by Ang II. Furthermore, we demonstrated that CTGF expression was essential for Ang II-mediated ECM synthesis. Interestingly, the ability of dephosphorylated, but not phosphorylated JNK to activate Smad2\/3 signaling revealed a novel role of JNK in Ang II-mediated CTGF overexpression. These results suggest that Ang II induces CTGF expression and ECM accumulation through a special TGF-<jats:italic>\u03b2<\/jats:italic>-independent interaction between the NF-<jats:italic>\u03ba<\/jats:italic>B and Smad2\/3 signals elicited by the AT<jats:sub>1<\/jats:sub>\/PKC<jats:italic>\u03b1<\/jats:italic>\/p38 MAPK pathway.<\/jats:p>","DOI":"10.1038\/s41598-017-08334-x","type":"journal-article","created":{"date-parts":[[2017,8,4]],"date-time":"2017-08-04T14:58:54Z","timestamp":1501858734000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Angiotensin II induces connective tissue growth factor expression in human hepatic stellate cells by a transforming growth factor \u03b2-independent mechanism"],"prefix":"10.1038","volume":"7","author":[{"given":"Ao","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingyao","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxun","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Songsong","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5235-6311","authenticated-orcid":false,"given":"Peng","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yitao","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,8,10]]},"reference":[{"key":"8334_CR1","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1016\/j.abb.2014.02.015","volume":"548","author":"E Novo","year":"2014","unstructured":"Novo, E. et al. 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