Published online before print July 9, 2009

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(American Journal of Pathology. 2009;175:580-591.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.080983

Disruption of E-Cadherin by Matrix Metalloproteinase Directly Mediates Epithelial-Mesenchymal Transition Downstream of Transforming Growth Factor-β1 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,^* and the Gene Expression Laboratory,^¶ the University of Sydney at Westmead Millennium Institute, Sydney; the Sydney Head & Neck Cancer Institute, Sydney Cancer Center, Royal Prince Alfred Hospital and Dermatology Research Laboratories, and the Department of Endocrinology, University of Sydney, Sydney; the Center for Kidney Research, The Children’s Hospital at Westmead, University of Sydney, Sydney, New South Wales, Australia

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)-β1-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-β1 induced the proteolytic shedding of E-cadherin, which caused the nuclear translocation of β-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-β1 in fibrotic disease. Specific inhibition rather than activation of matrix metalloproteinases may offer a novel approach for treatment of fibrotic disease.

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