Document Detail


Essential role for Smad3 in angiotensin II-induced tubular epithelial-mesenchymal transition.
MedLine Citation:
PMID:  20593491     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Angiotensin II (Ang II) is a key mediator of chronic kidney disease, in which epithelial-mesenchymal transition (EMT) is a critical process mediated by the TGFbeta/Smad signalling pathway. The present study examined the specific role of Smads in Ang II-induced EMT in vitro and in vivo. We found that Ang II signalled through the receptor of AT1, not AT2, to activate Smad2/3 and induce EMT in a normal rat tubular epithelial cell line (NRK52E). Activation of Smads by Ang II was attributed to degradation of an inhibitory Smad7, which was mediated by the AT1-Smurf2-dependent ubiquitin degradation mechanism because blockade of AT1 receptor or knockdown of Smurf2 inhibited Smad7 loss, thereby reducing Smad2/3 activation and EMT in response to Ang II. In contrast, over-expression of Smad7 inhibited Ang II-induced Smad2/3 activation and EMT in NRK52E cells and in a rat model of remnant kidney disease. Moreover, knockdown of Smad3, not Smad2, attenuated Ang II-induced EMT. In conclusion, Ang II activates Smad signalling to induce EMT, which is mediated by a loss of Smad7 through the AT1-Smurf2-dependent ubiquitin degradation pathway. Smad3, but not Smad2, may be a mediator of EMT, while Smad7 may play a protective role in EMT in response to Ang II.
Authors:
Fuye Yang; Xiao Ru Huang; Arthur C K Chung; Chun-Cheng Hou; Kar Neng Lai; Hui Yao Lan
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Journal of pathology     Volume:  221     ISSN:  1096-9896     ISO Abbreviation:  J. Pathol.     Publication Date:  2010 Aug 
Date Detail:
Created Date:  2010-07-07     Completed Date:  2010-08-02     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0204634     Medline TA:  J Pathol     Country:  England    
Other Details:
Languages:  eng     Pagination:  390-401     Citation Subset:  IM    
Affiliation:
Department of Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Shatin, NT, Hong Kong.
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MeSH Terms
Descriptor/Qualifier:
Angiotensin II / pharmacology*
Animals
Cells, Cultured
Dose-Response Relationship, Drug
Epithelium / drug effects,  pathology
Gene Therapy / methods
Kidney Diseases / metabolism,  therapy
Kidney Tubules / drug effects*,  pathology,  physiopathology
Male
Mesoderm / drug effects,  pathology
Rats
Rats, Sprague-Dawley
Receptor, Angiotensin, Type 1 / drug effects,  physiology
Receptor, Angiotensin, Type 2 / drug effects,  physiology
Signal Transduction / drug effects,  physiology
Smad Proteins, Receptor-Regulated / physiology
Smad2 Protein / metabolism
Smad3 Protein / physiology*
Smad7 Protein / metabolism
Ubiquitin / metabolism
Chemical
Reg. No./Substance:
0/Madh3 protein, rat; 0/Receptor, Angiotensin, Type 1; 0/Receptor, Angiotensin, Type 2; 0/Smad Proteins, Receptor-Regulated; 0/Smad2 Protein; 0/Smad3 Protein; 0/Smad7 Protein; 0/Ubiquitin; 11128-99-7/Angiotensin II

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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