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Vol. 18, Issue 3, 1083-1097, March 2007
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*St. Michael's Hospital Research Institute, Toronto, ON, Canada M5B 1W8; Department of Surgery, University of Toronto, ON, Canada M5G 1L5; Nephrology Research Center, Semmelweis University, Budapest, Hungary H-1089; ||Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan 113-8421; ¶CIHR Group in Matrix Dynamics, University of Toronto, Toronto, ON, Canada M5S 3E2; and #First Department of Internal Medicine, Semmelweis University, Budapest, Hungary H-1083
Submitted July 17, 2006;
Revised December 15, 2006;
Accepted January 3, 2007
Monitoring Editor: Asma Nusrat
Epithelial-mesenchymal-myofibroblast transition (EMT), a key feature in organ fibrosis, is regulated by the state of intercellular contacts. Our recent studies have shown that an initial injury of cell–cell junctions is a prerequisite for transforming growth factor-
1 (TGF-1)-induced transdifferentiation of kidney tubular cells into 
-smooth muscle actin (SMA)–expressing myofibroblasts. Here we analyzed the underlying contact-dependent mechanisms. Ca2+ removal–induced disruption of intercellular junctions provoked Rho/Rho kinase (ROK)-mediated myosin light chain (MLC) phosphorylation and Rho/ROK-dependent SMA promoter activation. Importantly, myosin-based contractility itself played a causal role, because the myosin ATPase inhibitor blebbistatin or a nonphosphorylatable, dominant negative MLC (DN-MLC) abolished the contact disruption-triggered SMA promoter activation, eliminated the synergy between contact injury and TGF-1, and suppressed SMA expression. To explore the responsible mechanisms, we investigated the localization of the main SMA-inducing transcription factors, serum response factor (SRF), and its coactivator myocardin-related transcription factor (MRTF). Contact injury enhanced nuclear accumulation of SRF and MRTF. These processes were inhibited by DN-Rho or DN-MLC. TGF-1 strongly facilitated nuclear accumulation of MRTF in cells with reduced contacts but not in intact epithelia. DN-myocardin abrogated the Ca2+-removal– ± TGF-1–induced promoter activation. These studies define a new mechanism whereby cell contacts regulate epithelial-myofibroblast transition via Rho-ROK-phospho-MLC–dependent nuclear accumulation of MRTF.
These authors contributed equally to this work.
Address correspondence to: András Kapus (kapusa{at}smh.toronto.on.ca)
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