Disruption of E-cadherin by matrix metalloproteinase directly mediates epithelial-mesenchymal transition downstream of transforming growth factor-beta1 in renal tubular epithelial cells.
Epithelial-mesenchymal transition (EMT) plays an important role in organ fibrosis, including that of the kidney. Loss of E-cadherin expression is a hallmark of EMT; however, whether the loss of E-cadherin is a consequence or a cause of EMT remains unknown, especially in the renal system. In this study, we show that transforming growth factor (TGF)-beta1-induced EMT in renal tubular epithelial cells is dependent on proteolysis. Matrix metalloproteinase-mediated E-cadherin disruption led directly to tubular epithelial cell EMT via Slug. TGF-beta1 induced the proteolytic shedding of E-cadherin, which caused the nuclear translocation of beta-catenin, the transcriptional induction of Slug, and the repression of E-cadherin transcription in tubular epithelial cells. These findings reveal a direct role for E-cadherin and for matrix metalloproteinases in causing EMT downstream of TGF-beta1 in fibrotic disease. Specific inhibition rather than activation of matrix metalloproteinases may offer a novel approach for treatment of fibrotic disease.
Zheng
Guoping
G
Centre for Transplantation and Renal Research, the University of Sydney at Westmead Millennium Institute, Westmead, NSW 2145 Australia. guoping_zheng@wmi.usyd.edu.au
Lyons
James Guy
JG
Tan
Thian Kui
TK
Wang
Yiping
Y
Hsu
Tzu-Ting
TT
Min
Danqing
D
Succar
Lena
L
Rangan
Gopala K
GK
Hu
Min
M
Henderson
Beric R
BR
Alexander
Stephen I
SI
Harris
David C H
DC
D021581:Active Transport, Cell Nucleus; D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D054337:Cell Dedifferentiation; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D004848:Epithelium / Q000473:pathology*; D005355:Fibrosis; D007684:Kidney Tubules / Q000473:pathology*; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D008648:Mesoderm / Q000473:pathology*; D051381:Rats; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D015854:Up-Regulation; D051176:beta Catenin / Q000378:metabolism
D015820:Cadherins; C000604450:Snai2 protein, rat; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; D051176:beta Catenin; D019278:Matrix Metalloproteinase 3; D020780:Matrix Metalloproteinase 9