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

作者：Zheng Guoping^*; Lyons James Guy; Tan Thian Kui; Wang Yiping; Hsu Tzu Ting; Min Danqing; Succar Lena; Rangan Gopala K; Hu Min; Henderson Beric R; Alexander Stephen I; Harris David C H

来源：American Journal Of Pathology, 2009, 175(2): 580-591.

DOI：10.2353/ajpath.2009.080983

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)-beta 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-beta 1 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-beta 1 in fibrotic disease. Specific inhibition rather than activation of matrix metalloproteinases may offer a novel approach for treatment of fibrotic disease. (Am J Pathol 2009,175:580-591; DOI: 10.2353/ajpath.2009.080983)

• 出版日期2009-8