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 TGFbeta/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.
Yang
Fuye
F
Department of Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Shatin, NT, Hong Kong.
Huang
Xiao Ru
XR
Chung
Arthur C K
AC
Hou
Chun-Cheng
CC
Lai
Kar Neng
KN
Lan
Hui Yao
HY
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004848:Epithelium / Q000187:drug effects / Q000473:pathology; D015316:Genetic Therapy / Q000379:methods; D007674:Kidney Diseases / Q000378:metabolism / Q000628:therapy; D007684:Kidney Tubules / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008648:Mesoderm / Q000187:drug effects / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects / Q000502:physiology; D044139:Receptor, Angiotensin, Type 2 / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D051896:Smad Proteins, Receptor-Regulated / Q000502:physiology; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000502:physiology*; D051906:Smad7 Protein / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism
D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D051896:Smad Proteins, Receptor-Regulated; D051899:Smad2 Protein; D051900:Smad3 Protein; C497787:Smad3 protein, rat; D051906:Smad7 Protein; D025801:Ubiquitin; D000804:Angiotensin II