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. Copyright © American Society for Investigative Pathology.
CITATION STYLE
Zheng, G., Lyons, J. G., Thian, K. T., Wang, Y., Hsu, T. T., Min, D., … Harris, D. C. H. (2009). Disruption of E-cadherin by matrix metalloproteinase directly mediates epithelial-mesenchymal transition downstream of transforming growth factor-β1 in renal tubular epithelial cells. American Journal of Pathology, 175(2), 580–591. https://doi.org/10.2353/ajpath.2009.080983
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