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

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 An...

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Bibliographic Details
Published in:The Journal of pathology 2010-08, Vol.221 (4), p.390-401
Main Authors: Yang, Fuye, Huang, Xiao Ru, Chung, Arthur CK, Hou, Chun-Cheng, Lai, Kar Neng, Lan, Hui Yao
Format: Article
Language:English
Subjects:
angiotensin II
Angiotensin II - pharmacology
Animals
Biological and medical sciences
Cells, Cultured
Dose-Response Relationship, Drug
EMT
Epithelium - drug effects
Epithelium - pathology
Genetic Therapy - methods
Investigative techniques, diagnostic techniques (general aspects)
Kidney Diseases - metabolism
Kidney Diseases - therapy
Kidney Tubules - drug effects
Kidney Tubules - pathology
Kidney Tubules - physiopathology
Kidneys
Male
Medical sciences
Mesoderm - drug effects
Mesoderm - pathology
Nephrology. Urinary tract diseases
Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques
Rats
Rats, Sprague-Dawley
Receptor, Angiotensin, Type 1 - drug effects
Receptor, Angiotensin, Type 1 - physiology
Receptor, Angiotensin, Type 2 - drug effects
Receptor, Angiotensin, Type 2 - physiology
renal fibrosis
Signal Transduction - drug effects
Signal Transduction - physiology
signalling pathway
Smad
Smad Proteins, Receptor-Regulated - physiology
Smad2 Protein - metabolism
Smad3 Protein - physiology
Smad7 Protein - metabolism
Ubiquitin - metabolism
Urinary system involvement in other diseases. Miscellaneous
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Summary: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. Copyright © 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
ISSN:0022-3417
1096-9896
DOI:10.1002/path.2721