Angiotensin II Induces Connective Tissue Growth Factor and Collagen I Expression via Transforming Growth Factor-beta-Dependent and -Independent Smad Pathways The Role of Smad3
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摘要Connective tissue growth factor (CTGF) plays a critical role in angiotensin II (Ang II)-mediated hypertensive nephropathy. The present study investigated the mechanisms and specific roles of individual Smads in Ang II-induced CTGF and collagen I expression in tubular epithelial cells with deletion of transforming growth factor (TGF)-beta 1, overexpression of Smad7, or knockdown of Smad2 or Smad3. We found that Ang II-induced tubular CTGF and collagen I mRNA and protein expressions were regulated positively by phosphorylated Smad2/3 but negatively by Smad7 because overexpression of Smad7-abolished Ang II-induced Smad2/3 phosphorylation and upregulation of CTGF and collagen I in vitro and in a rat model of remnant kidney disease. Additional studies revealed that, in addition to a late (24-hour) TGF-beta-dependent Smad2/3 activation, Ang II also induced a rapid activation of Smad2/3 at 15 minutes and expression of CTGF and collagen I in tubular epithelial cells lacking the TGF-beta gene, which was blocked by the addition of an Ang II type 1 receptor antagonist (losartan) and inhibitors to extracellular signal-regulated kinase 1/2 (PD98059) and p38 (SB203580) but not by inhibitors to Ang II type 2 receptor (PD123319) or c-Jun N-terminal kinase (SP600125), demonstrating a TGF-beta-independent, Ang II type 1 receptor-mediated extracellular signal regulated kinase/p38 mitogen-activated protein kinase cross-talk pathway in Ang II-mediated CTGF and collagen I expression. Importantly, the ability of knockdown of Smad3, but not Smad2, to inhibit Ang II-induced CTGF and collagen I expression further revealed an essential role for Smad3 in Ang II-mediated renal fibrosis. In conclusion, Ang II induces tubular CTGF expression and renal fibrosis via the TGF-beta-dependent and-independent Smad3 signaling pathways, suggesting that targeting Smad3 may have therapeutic potential for hypertensive nephropathy. (Hypertension. 2009; 54: 877-884.)
著者Yang FY, Chung ACK, Huang XR, Lan HY
期刊名稱Hypertension
出版年份2009
月份10
日期1
卷號54
期次4
出版社American Heart Association
頁次877 - 884
國際標準期刊號0194-911X
電子國際標準期刊號1524-4563
語言英式英語
關鍵詞angiotensin II; CTGF; MAP kinases; renal fibrosis; Smads; TGF-beta
Web of Science 學科類別Cardiovascular System & Cardiology; Peripheral Vascular Disease; PERIPHERAL VASCULAR DISEASE

上次更新時間 2021-13-01 於 00:32