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1-Induced Smooth Muscle Actin Expression During Epithelial-Mesenchymal Transition
1 Department of Surgery, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada; Department of Pathophysiology, Semmelweis University, Budapest, Hungary
2 Department of Surgery, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
3 Department of Cell and Developmental Biology, University of North Carolina, Chapel Hill, North Carolina, USA
4 CIHR Group in Matrix Dynamics, Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada
5 Department of Pathophysiology, Semmelweis University, Budapest, Hungary
6 Department of Pathophysiology, Semmelweis University, Budapest, Hungary; 1st Department of Internal Medicine, Semmelweis University, Budapest, Hungary; Department of Behavioural Sciences, Semmelweis University, Budapest, Hungary
* To whom correspondence should be addressed. E-mail: akapus{at}transplantunit.org.
New research suggests that during tubulointerstitial fibrosis 
-smooth muscle actin (SMA)-expressing mesenchymal cells might derive from the tubular epithelium via epithelial-mesenchymal transition (EMT). While transforming growth factor-
1 (TGF-1) plays a key role in EMT, the underlying cellular mechanisms are not well understood. Here we characterized TGF-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-1 treatment caused delocalization and down-regulation of cell contact proteins (ZO-1, E-cadherin, -catenin), cytoskeleton reorganization (stress fiber assembly, myosin light chain (MLC) phosphorylation), and robust SMA synthesis. TGF-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 strongly activated by constitutively active Rho but not ROK. Accordingly, TGF-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-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, while the transcriptional effects are partially ROK-independent.
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