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Article: Essential role for Smad3 in angiotensin II-induced tubular epithelial-mesenchymal transition
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TitleEssential role for Smad3 in angiotensin II-induced tubular epithelial-mesenchymal transition
 
AuthorsYang, F1
Huang, XR4
Chung, ACK4
Hou, CC2 3
Lai, KN1
Lan, HY1 4
 
KeywordsAngiotensin II
EMT
Renal fibrosis
Signalling pathway
Smad
 
Issue Date2010
 
PublisherJohn Wiley & Sons. The Journal's web site is located at http://www3.interscience.wiley.com/cgi-bin/jhome/1130
 
CitationJournal Of Pathology, 2010, v. 221 n. 4, p. 390-401 [How to Cite?]
DOI: http://dx.doi.org/10.1002/path.2721
 
AbstractAngiotensin II (Ang II) is a key mediator of chronic kidney disease, in which epithelial-mesenchymal transition (EMT) is a critical process mediated by the TGFβ/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. Copyright © 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
 
ISSN0022-3417
2013 Impact Factor: 7.330
 
DOIhttp://dx.doi.org/10.1002/path.2721
 
ISI Accession Number IDWOS:000280010300005
Funding AgencyGrant Number
Research Grant Council of Hong Kong SARGRF768207
GRF767508
CUHK5/CRF/09
Baxter Renal Discoveries Programme
Funding Information:

This work was supported by grants from the Research Grant Council of Hong Kong SAR (Nos GRF768207, GRF767508 and CUHK5/CRF/09) and the Baxter Renal Discoveries Programme (2002).

 
ReferencesReferences in Scopus
 
DC FieldValue
dc.contributor.authorYang, F
 
dc.contributor.authorHuang, XR
 
dc.contributor.authorChung, ACK
 
dc.contributor.authorHou, CC
 
dc.contributor.authorLai, KN
 
dc.contributor.authorLan, HY
 
dc.date.accessioned2011-10-03T09:58:56Z
 
dc.date.available2011-10-03T09:58:56Z
 
dc.date.issued2010
 
dc.description.abstractAngiotensin II (Ang II) is a key mediator of chronic kidney disease, in which epithelial-mesenchymal transition (EMT) is a critical process mediated by the TGFβ/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. Copyright © 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
 
dc.description.natureLink_to_subscribed_fulltext
 
dc.identifier.citationJournal Of Pathology, 2010, v. 221 n. 4, p. 390-401 [How to Cite?]
DOI: http://dx.doi.org/10.1002/path.2721
 
dc.identifier.citeulike7853594
 
dc.identifier.doihttp://dx.doi.org/10.1002/path.2721
 
dc.identifier.epage401
 
dc.identifier.hkuros196747
 
dc.identifier.isiWOS:000280010300005
Funding AgencyGrant Number
Research Grant Council of Hong Kong SARGRF768207
GRF767508
CUHK5/CRF/09
Baxter Renal Discoveries Programme
Funding Information:

This work was supported by grants from the Research Grant Council of Hong Kong SAR (Nos GRF768207, GRF767508 and CUHK5/CRF/09) and the Baxter Renal Discoveries Programme (2002).

 
dc.identifier.issn0022-3417
2013 Impact Factor: 7.330
 
dc.identifier.issue4
 
dc.identifier.openurl
 
dc.identifier.pmid20593491
 
dc.identifier.scopuseid_2-s2.0-77955489258
 
dc.identifier.spage390
 
dc.identifier.urihttp://hdl.handle.net/10722/141986
 
dc.identifier.volume221
 
dc.languageeng
 
dc.publisherJohn Wiley & Sons. The Journal's web site is located at http://www3.interscience.wiley.com/cgi-bin/jhome/1130
 
dc.publisher.placeUnited Kingdom
 
dc.relation.ispartofJournal of Pathology
 
dc.relation.referencesReferences in Scopus
 
dc.rightsJournal of Pathology. Copyright © John Wiley & Sons.
 
dc.subject.meshAngiotensin II - pharmacology
 
dc.subject.meshGene Therapy - methods
 
dc.subject.meshKidney Diseases - metabolism - therapy
 
dc.subject.meshKidney Tubules - drug effects - pathology - physiopathology
 
dc.subject.meshSmad3 Protein - physiology
 
dc.subjectAngiotensin II
 
dc.subjectEMT
 
dc.subjectRenal fibrosis
 
dc.subjectSignalling pathway
 
dc.subjectSmad
 
dc.titleEssential role for Smad3 in angiotensin II-induced tubular epithelial-mesenchymal transition
 
dc.typeArticle
 
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<contributor.author>Hou, CC</contributor.author>
<contributor.author>Lai, KN</contributor.author>
<contributor.author>Lan, HY</contributor.author>
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Author Affiliations
  1. The University of Hong Kong Li Ka Shing Faculty of Medicine
  2. Min-Sheng General Hospital
  3. Taipei Medical University
  4. Chinese University of Hong Kong