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Article: Essential role for Smad3 in angiotensin II-induced tubular epithelial-mesenchymal transition

TitleEssential role for Smad3 in angiotensin II-induced tubular epithelial-mesenchymal transition
Authors
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
Citation
Journal Of Pathology, 2010, v. 221 n. 4, p. 390-401 How to Cite?
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.
Persistent Identifierhttp://hdl.handle.net/10722/141986
ISSN
2014 Impact Factor: 7.429
2014 SCImago Journal Rankings: 3.612
ISI Accession Number ID
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).

References

 

DC FieldValueLanguage
dc.contributor.authorYang, Fen_HK
dc.contributor.authorHuang, XRen_HK
dc.contributor.authorChung, ACKen_HK
dc.contributor.authorHou, CCen_HK
dc.contributor.authorLai, KNen_HK
dc.contributor.authorLan, HYen_HK
dc.date.accessioned2011-10-03T09:58:56Z-
dc.date.available2011-10-03T09:58:56Z-
dc.date.issued2010en_HK
dc.identifier.citationJournal Of Pathology, 2010, v. 221 n. 4, p. 390-401en_HK
dc.identifier.issn0022-3417en_HK
dc.identifier.urihttp://hdl.handle.net/10722/141986-
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.en_HK
dc.languageeng-
dc.publisherJohn Wiley & Sons. The Journal's web site is located at http://www3.interscience.wiley.com/cgi-bin/jhome/1130en_HK
dc.relation.ispartofJournal of Pathologyen_HK
dc.rightsJournal of Pathology. Copyright © John Wiley & Sons.-
dc.subjectAngiotensin IIen_HK
dc.subjectEMTen_HK
dc.subjectRenal fibrosisen_HK
dc.subjectSignalling pathwayen_HK
dc.subjectSmaden_HK
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.titleEssential role for Smad3 in angiotensin II-induced tubular epithelial-mesenchymal transitionen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0022-3417&volume=221&issue=4&spage=390&epage=401&date=2010&atitle=Essential+role+for+Smad3+in+angiotensin+II-induced+tubular+epithelial-mesenchymal+transition-
dc.identifier.emailLai, KN: knlai@hku.hken_HK
dc.identifier.authorityLai, KN=rp00324en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1002/path.2721en_HK
dc.identifier.pmid20593491en_HK
dc.identifier.scopuseid_2-s2.0-77955489258en_HK
dc.identifier.hkuros196747-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-77955489258&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume221en_HK
dc.identifier.issue4en_HK
dc.identifier.spage390en_HK
dc.identifier.epage401en_HK
dc.identifier.isiWOS:000280010300005-
dc.publisher.placeUnited Kingdomen_HK
dc.identifier.scopusauthoridYang, F=35182193900en_HK
dc.identifier.scopusauthoridHuang, XR=7410248090en_HK
dc.identifier.scopusauthoridChung, ACK=7103291604en_HK
dc.identifier.scopusauthoridHou, CC=7202210159en_HK
dc.identifier.scopusauthoridLai, KN=7402135706en_HK
dc.identifier.scopusauthoridLan, HY=35783008500en_HK
dc.identifier.citeulike7853594-

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