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Article: Smad7 inhibits fibrotic effect of TGF-β on renal tubular epithelial cells by blocking Smad2 activation

TitleSmad7 inhibits fibrotic effect of TGF-β on renal tubular epithelial cells by blocking Smad2 activation
Authors
Issue Date2002
PublisherAmerican Society of Nephrology. The Journal's web site is located at http://www.jasn.org
Citation
Journal Of The American Society Of Nephrology, 2002, v. 13 n. 6, p. 1464-1472 How to Cite?
AbstractIt has been shown that transforming growth factor-β (TGF-β) is a potent mediator in renal fibrosis and that Smad proteins are critical intracellular mediators in TGF-β signaling. It is here reported that TGF-β mediates renal fibrogenesis in tubular epithelial cells (TEC) in association with the activation of Smad2 and that overexpression of Smad7 blocks this fibrotic process. Using a normal rat kidney tubular epithelial cell line (NRK52E), it was determined that TGF-β induces Smad2 phosphorylation and nuclear localization in both a dose- and time-dependent manner. The activation of Smad2 was evident at 5 min (20%), peaked at 15 to 30 min (85%), and declined to baseline levels by 2 h (5 to 10%). This was associated with de novo expression of collagens I, III, and IV and the transformation of TEC into a "myofibroblast" phenotype with de novo expression of α-smooth muscle actin (α-SMA) and with the loss of E-cadherin (>50%). To investigate a negative regulatory role of Smad7 in renal fibrosis, the Smad 7 gene was stably transfected and its expression was tightly controlled by doxycycline into NRK52E cells. Overexpression of Smad7 induced by doxycycline results in marked inhibition of TGF-β-induced Smad2 activation (90% ↓) with the prevention of collagen synthesis and myofibroblast transformation. Thus, Smad2 activation occurs in the fibrogenic response of TEC to TGF-β, and this process is blocked by overexpression of Smad7. This indicates that Smad signaling is a key pathway of TGF-β-mediated renal fibrosis and suggests that treatments targeting the inactivation of Smad2 by overexpression of Smad7 may provide a new therapeutic strategy for renal fibrosis.
Persistent Identifierhttp://hdl.handle.net/10722/78304
ISSN
2015 Impact Factor: 8.491
2015 SCImago Journal Rankings: 4.699
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorLi, JHen_HK
dc.contributor.authorZhu, HJen_HK
dc.contributor.authorHuang, XRen_HK
dc.contributor.authorLai, KNen_HK
dc.contributor.authorJohnson, RJen_HK
dc.contributor.authorLan, HYen_HK
dc.date.accessioned2010-09-06T07:41:24Z-
dc.date.available2010-09-06T07:41:24Z-
dc.date.issued2002en_HK
dc.identifier.citationJournal Of The American Society Of Nephrology, 2002, v. 13 n. 6, p. 1464-1472en_HK
dc.identifier.issn1046-6673en_HK
dc.identifier.urihttp://hdl.handle.net/10722/78304-
dc.description.abstractIt has been shown that transforming growth factor-β (TGF-β) is a potent mediator in renal fibrosis and that Smad proteins are critical intracellular mediators in TGF-β signaling. It is here reported that TGF-β mediates renal fibrogenesis in tubular epithelial cells (TEC) in association with the activation of Smad2 and that overexpression of Smad7 blocks this fibrotic process. Using a normal rat kidney tubular epithelial cell line (NRK52E), it was determined that TGF-β induces Smad2 phosphorylation and nuclear localization in both a dose- and time-dependent manner. The activation of Smad2 was evident at 5 min (20%), peaked at 15 to 30 min (85%), and declined to baseline levels by 2 h (5 to 10%). This was associated with de novo expression of collagens I, III, and IV and the transformation of TEC into a "myofibroblast" phenotype with de novo expression of α-smooth muscle actin (α-SMA) and with the loss of E-cadherin (>50%). To investigate a negative regulatory role of Smad7 in renal fibrosis, the Smad 7 gene was stably transfected and its expression was tightly controlled by doxycycline into NRK52E cells. Overexpression of Smad7 induced by doxycycline results in marked inhibition of TGF-β-induced Smad2 activation (90% ↓) with the prevention of collagen synthesis and myofibroblast transformation. Thus, Smad2 activation occurs in the fibrogenic response of TEC to TGF-β, and this process is blocked by overexpression of Smad7. This indicates that Smad signaling is a key pathway of TGF-β-mediated renal fibrosis and suggests that treatments targeting the inactivation of Smad2 by overexpression of Smad7 may provide a new therapeutic strategy for renal fibrosis.en_HK
dc.languageengen_HK
dc.publisherAmerican Society of Nephrology. The Journal's web site is located at http://www.jasn.orgen_HK
dc.relation.ispartofJournal of the American Society of Nephrologyen_HK
dc.titleSmad7 inhibits fibrotic effect of TGF-β on renal tubular epithelial cells by blocking Smad2 activationen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=1046-6673&volume=13&issue=6&spage=1464&epage=1472&date=2002&atitle=Smad7+inhibits+fibrotic+effect+of+TGF-beta+on+renal+tubular+epithelial+cells+by+blocking+smad2+activationen_HK
dc.identifier.emailLai, KN: knlai@hku.hken_HK
dc.identifier.authorityLai, KN=rp00324en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1097/01.ASN.0000014252.37680.E4en_HK
dc.identifier.pmid12039975en_HK
dc.identifier.scopuseid_2-s2.0-0036014928en_HK
dc.identifier.hkuros69582en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-0036014928&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume13en_HK
dc.identifier.issue6en_HK
dc.identifier.spage1464en_HK
dc.identifier.epage1472en_HK
dc.identifier.isiWOS:000175917800006-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridLi, JH=7410065460en_HK
dc.identifier.scopusauthoridZhu, HJ=8207348000en_HK
dc.identifier.scopusauthoridHuang, XR=7410248090en_HK
dc.identifier.scopusauthoridLai, KN=7402135706en_HK
dc.identifier.scopusauthoridJohnson, RJ=35398596600en_HK
dc.identifier.scopusauthoridLan, HY=7102710832en_HK

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