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Angiotensin II activates connective tissue growth factor and induces extracellular matrix changes involving Smad/activation and p38 mitogen‐activated protein kinase signalling pathways in human dermal fibroblasts
Author(s) -
Zhang GuoYou,
Li Xuan,
Yi ChengGang,
Pan Hua,
He GuoDong,
Yu Qing,
Jiang LiangFu,
Xu WeiHua,
Li ZhiJie,
Ding Jian,
Lin DingSheng,
Gao WeiYang
Publication year - 2009
Publication title -
experimental dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.108
H-Index - 96
eISSN - 1600-0625
pISSN - 0906-6705
DOI - 10.1111/j.1600-0625.2009.00880.x
Subject(s) - angiotensin ii , smad , losartan , mapk/erk pathway , protein kinase a , microbiology and biotechnology , chemistry , endocrinology , growth factor , transforming growth factor , medicine , kinase , biology , receptor
Angiotensin II (Ang II) stimulation has been shown to regulate proliferation of skin fibroblasts and the production of extracellular matrix, which are very important processes in skin wound healing and fibrosis; however, there is little knowledge about the mechanisms involved in this process. We investigated the molecular aspects of this system with regards to Ang II in human dermal fibroblasts (HDF) and its potential role in fibrosis. Fibroblasts derived from human skin were subjected to examine differential relative gene and protein expression after transfection with specific reporter expression vectors and Ang II in vitro . In growth‐arrested HDFs, Ang II treatment for 20 min caused acute activation of Smad2 phosphorylation, Smad overexpression and Smad‐dependent gene transcription. The angiotensin type 1 (AT1) antagonist losartan diminished Ang II‐induced Smad activation. The blockade of endogenous transforming growth factor‐β1 did modify the activation of Smad caused by Ang II. The p38 mitogen‐activated protein kinase (MAPK) inhibitor SB203580 diminished Ang II‐induced Smad2 phosphorylation. Transient transfection with Smad7, which interferes with receptor‐mediated activation of Smad2, diminished Ang II‐induced connective tissue growth factor promoter activation, gene and protein expression and fibronectin, type I procollagen and type III procollagen overexpression, showing that Smad activation is involved in Ang II‐induced dermal fibrosis. Our results show that Ang II activation of Smad2 occurs via the AT1 receptor, but not the AT2 receptor. Activation of Smad2 required p38 MAPK but not p42/p44 MAPK or the epidermal growth factor receptor.