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

69 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

Fingerprint

Epithelial-Mesenchymal Transition
Angiotensin II
Ubiquitin
Kidney Diseases
Chronic Renal Insufficiency
Epithelial Cells
Cell Line

Keywords

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

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Yang, F., Huang, X. R., Chung, A. C. K., Hou, C. C., Lai, K. N., & Lan, H. Y. (2010). Essential role for Smad3 in angiotensin II-induced tubular epithelial-mesenchymal transition. Journal of Pathology, 221(4), 390-401. https://doi.org/10.1002/path.2721

Essential role for Smad3 in angiotensin II-induced tubular epithelial-mesenchymal transition. / Yang, Fuye; Huang, Xiao Ru; Chung, Arthur C K; Hou, Chun Cheng; Lai, Kar Neng; Lan, Hui Yao.

In: Journal of Pathology, Vol. 221, No. 4, 08.2010, p. 390-401.

Research output: Contribution to journalArticle

Yang, F, Huang, XR, Chung, ACK, Hou, CC, Lai, KN & Lan, HY 2010, 'Essential role for Smad3 in angiotensin II-induced tubular epithelial-mesenchymal transition', Journal of Pathology, vol. 221, no. 4, pp. 390-401. https://doi.org/10.1002/path.2721
Yang, Fuye ; Huang, Xiao Ru ; Chung, Arthur C K ; Hou, Chun Cheng ; Lai, Kar Neng ; Lan, Hui Yao. / Essential role for Smad3 in angiotensin II-induced tubular epithelial-mesenchymal transition. In: Journal of Pathology. 2010 ; Vol. 221, No. 4. pp. 390-401.
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