Published online before print July 9, 2009

This Article Full Text (Rapid PDF) Supplemental Material All Versions of this Article: ajpath.2009.080983v1 175/2/580    most recent Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zheng, G. Articles by Harris, D. C.H. Search for Related Content PubMed PubMed Citation Articles by Zheng, G. Articles by Harris, D. C.H.

Copyright © 2009 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2009.080983

Accepted for publication April 22, 2009.

Article

Disruption of E-Cadherin by Matrix Metalloproteinase Directly Mediates Epithelial-Mesenchymal Transition Downstream of Transforming Growth Factor-1 in Renal Tubular Epithelial Cells

Guoping Zheng^*@, James Guy Lyons, Thian Kui Tan^*, Yiping Wang^*, Tzu-Ting Hsu^*, Danqing Min, Lena Succar^*, Gopala K. Rangan^*, Min Hu, Beric R. Henderson^¶, Stephen I. Alexander, and David C.H. Harris^*

From the Center for Transplantation and Renal Research,* the University of Sydney at Westmead Millennium Institute; the Sydney Head & Neck Cancer Institute, Sydney Cancer Center, Royal Prince Alfred Hospital, and Dermatology Research Laboratories, University of Sydney; the Department of Endocrinology, University of Sydney; the Center for Kidney Research, The Children's Hospital at Westmead, University of Sydney; and the Westmead Millennium Institute,^¶ University of Sydney, Sydney, New South Wales, Australia

^@ To whom correspondence should be addressed. E-mail: guoping_zheng{at}wmi.usyd.edu.au.

	Abstract

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)-1-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-1 induced the proteolytic shedding of E-cadherin, which caused the nuclear translocation of -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-1 in fibrotic disease. Specific inhibition rather than activation of matrix metalloproteinases may offer a novel approach for treatment of fibrotic disease.

This article has been cited by other articles:

				M. H. U. Biswas, C. Du, C. Zhang, J. Straubhaar, L. R. Languino, and K.C. Balaji Protein Kinase D1 Inhibits Cell Proliferation through Matrix Metalloproteinase-2 and Matrix Metalloproteinase-9 Secretion in Prostate Cancer Cancer Res., March 1, 2010; 70(5): 2095 - 2104. [Abstract] [Full Text] [PDF]

				T. K. Tan, G. Zheng, T.-T. Hsu, Y. Wang, V. W.S. Lee, X. Tian, Y. Wang, Q. Cao, Y. Wang, and D. C.H. Harris Macrophage Matrix Metalloproteinase-9 Mediates Epithelial-Mesenchymal Transition in Vitro in Murine Renal Tubular Cells Am. J. Pathol., March 1, 2010; 176(3): 1256 - 1270. [Abstract] [Full Text] [PDF]

				Y. Liu New Insights into Epithelial-Mesenchymal Transition in Kidney Fibrosis J. Am. Soc. Nephrol., February 1, 2010; 21(2): 212 - 222. [Abstract] [Full Text] [PDF]