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Am J Physiol Renal Physiol 284: F911-F924, 2003. First published December 27, 2002; doi:10.1152/ajprenal.00183.2002
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Vol. 284, Issue 5, F911-F924, May 2003

Central role for Rho in TGF-beta 1-induced alpha -smooth muscle actin expression during epithelial-mesenchymal transition

András Masszi1,2, Caterina Di Ciano1, Gábor Sirokmány1, William T. Arthur3, Ori D. Rotstein1, Jiaxu Wang4, Christopher A. G. McCulloch4, László Rosivall2, István Mucsi2,5,6, and András Kapus1

1 Department of Surgery, The Toronto General Hospital and University Health Network, Toronto, Ontario M5G 1L7; 4 Canadian Institutes of Health Research Group in Matrix Dynamics, Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada M5S 3E2; 2 Institute of Pathophysiology, Hungarian Academy of Sciences and Semmelweis University Nephrology Research Group, Budapest H-1089; 5 First Department of Internal Medicine, Faculty of Medicine and 6 Faculty of Medicine, Department of Behavioural Sciences, Semmelweis University, Budapest, Hungary H-1083; and 3 Department of Cell and Developmental Biology and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599

New research suggests that, during tubulointerstitial fibrosis, alpha -smooth muscle actin (SMA)-expressing mesenchymal cells might derive from the tubular epithelium via epithelial-mesenchymal transition (EMT). Although transforming growth factor-beta 1 (TGF-beta 1) plays a key role in EMT, the underlying cellular mechanisms are not well understood. Here we characterized TGF-beta 1-induced EMT in LLC-PK1 cells and examined the role of the small GTPase Rho and its effector, Rho kinase, (ROK) in the ensuing cytoskeletal remodeling and SMA expression. TGF-beta 1 treatment caused delocalization and downregulation of cell contact proteins (ZO-1, E-cadherin, beta -catenin), cytoskeleton reorganization (stress fiber assembly, myosin light chain phosphorylation), and robust SMA synthesis. TGF-beta 1 induced a biphasic Rho activation. Stress fiber assembly was prevented by the Rho-inhibiting C3 transferase and by dominant negative (DN) ROK. The SMA promoter was activated strongly by constitutively active Rho but not ROK. Accordingly, TGF-beta 1-induced SMA promoter activation was potently abrogated by two Rho-inhibiting constructs, C3 transferase and p190RhoGAP, but not by DN-ROK. Truncation analysis showed that the first CC(A/T)richGG (CArG B) serum response factor-binding cis element is essential for the Rho responsiveness of the SMA promoter. Thus Rho plays a dual role in TGF-beta 1-induced EMT of renal epithelial cells. It is indispensable both for cytoskeleton remodeling and for the activation of the SMA promoter. The cytoskeletal effects are mediated via the Rho/ROK pathway, whereas the transcriptional effects are partially ROK independent.

Rho kinase; epithelial-mesenchymal transdifferentiation; transforming growth factor-beta 1; kidney proximal tubule cells


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