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J. Biol. Chem., Vol. 283, Issue 16, 10461-10469, April 18, 2008

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AMP-activated Protein Kinase Inhibits Transforming Growth Factor-β-induced Smad3-dependent Transcription and Myofibroblast Transdifferentiation^*

Rangnath Mishra, Barbara L. Cool, Keith R. Laderoute^¶, Marc Foretz^||**, Benoit Viollet^||**, and Michael S. Simonson¹

From the Division of Nephrology and Hypertension, Department of Medicine, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland Ohio 44106, the Department of Metabolic Disease Research, Abbott Laboratories, Abbott Park, Illinois 60064, ^¶SRI International, Menlo Park, California 94025, ^||Institut Cochin, Universite Paris Descartes, CNRS (UMR 8104), 75014 Paris, France, and ^**INSERM, U567, 75014 Paris, France

In wound healing, myofibroblast transdifferentiation (MFT) is a metaplastic change in phenotype producing profibrotic effector cells that secrete and remodel the extracellular matrix. Unlike pathways that induce MFT, the molecular mechanisms that negatively regulate MFT are poorly understood. Here, we report that AMP-activated protein kinase (AMPK) blocks MFT in response to transforming growth factor-β (TGFβ). Pharmacological activation of AMPK inhibited TGFβ-induced secretion of extracellular matrix proteins collagen types I and IV and fibronectin. AMPK activation also prevented induction of the myofibroblast phenotype markers -smooth muscle actin and the ED-A fibronectin splice variant. AMPK activators did not prevent MFT in cells transduced with an adenovirus expressing dominant negative, kinase-dead AMPK2. Moreover, AMPK activators did not inhibit MFT induction in AMPK_1,2^–/– fibroblasts, demonstrating a requirement for AMPK expression. Adenoviral transduction of constitutively active AMPK₂ was sufficient to prevent TGFβ-induced collagen I, -smooth muscle actin, and ED-A fibronectin. AMPK did not reduce TGFβ-stimulated Smad3 COOH-terminal phosphorylation and nuclear translocation, which are necessary for MFT. However, AMPK activation inhibited TGFβ-induced transcription driven by Smad3-binding cis-elements. Consistent with a role for AMPK in transcriptional regulation, nuclear translocation of AMPK2 correlated with the appearance of active AMPK in the nucleus. Collectively, these results demonstrate that AMPK inhibits TGFβ-induced transcription downstream of Smad3 COOH-terminal phosphorylation and nuclear translocation. Furthermore, activation of AMPK is sufficient to negatively regulate MFT in vitro.

Received for publication, February 4, 2008

^* This work was supported by grants from the Rosenberg Foundation of the Centers for Dialysis Care (Cleveland, OH) and from the EXGENESIS Integrated Project (Grant LSHM-CT-2004-005272) funded by the European Commission (to B. V.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Medicine, Division of Nephrology, Biomedical Research Bldg., Rm. 427, Case Western Reserve University, 2109 Adelbert Rd., Cleveland, OH 44106. Tel.: 216-368-1251; Fax: 216-368-1249; E-mail: mss5{at}po.cwru.edu.

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