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

• 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
• ISSN: 0022-3417; 1096-9896
• DOI: 10.1002/path.2721

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.