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

Fuye Yang, Xiao Ru Huang, Arthur C K Chung, Chun Cheng Hou, Kar Neng Lai, Hui Yao Lan

Research output: Contribution to journalArticle

75 Citations (Scopus)

Abstract

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 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.

Original languageEnglish
Pages (from-to)390-401
Number of pages12
JournalJournal of Pathology
Volume221
Issue number4
DOIs
Publication statusPublished - Aug 2010

Keywords

  • Angiotensin II
  • EMT
  • Renal fibrosis
  • Signalling pathway
  • Smad

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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