title: Activation of AMP-activated protein kinase prevents TGF-β1-induced epithelial-mesenchymal transition and myofibroblast activation.
abstract: Transforming growth factor (TGF)-β contributes to tubulointerstitial fibrosis. We investigated the mechanism by which TGF-β exerts its profibrotic effects and specifically the role of AMP-activated protein kinase (AMPK) in kidney tubular epithelial cells and interstitial fibroblasts. In proximal tubular epithelial cells, TGF-β1 treatment causes a decrease in AMPK phosphorylation and activation together with increased fibronectin and α-smooth muscle actin expression and decreased in E-cadherin. TGF-β1 causes similar changes in interstitial fibroblasts. Activation of AMPK with 5-aminoimidazole-4-carboxamide 1-β-d-ribofuranoside, metformin, or overexpression of constitutively active AMPK markedly attenuated TGF-β1 functions. Conversely, inhibition of AMPK with adenine 9-β-d-arabinofuranoside or siRNA-mediated knockdown of AMPK (official name PRKAA1) mimicked the effect of TGF-β1 and enhanced basal and TGF-β1-induced phenotypic changes. Importantly, we found that tuberin contributed to the protective effects of AMPK and that TGF-β1 promoted cell injury by blocking AMPK-mediated tuberin phosphorylation and activation. In the kidney cortex of TGF-β transgenic mice, the significant decrease in AMPK phosphorylation and tuberin phosphorylation on its AMPK-dependent activating site was associated with an increase in mesenchymal markers and a decrease in E-cadherin. Collectively, the data indicate that TGF-β exerts its profibrotic action in vitro and in vivo via inactivation of AMPK. AMPK and tuberin activation prevent tubulointerstitial injury induced by TGF-β. Activators of AMPK provide potential therapeutic strategy to prevent kidney fibrosis and progressive kidney disease.
authors.affiliation: Department of Medicine, University of Texas Health Science Center, San Antonio, Texas.
authors.forename: Sachin
authors.initials: S
authors.lastname: Thakur
authors.affiliation: Department of Medicine, University of Texas Health Science Center, San Antonio, Texas. Electronic address: viswanadhapa@uthscsa.edu.
authors.forename: Suryavathi
authors.initials: S
authors.lastname: Viswanadhapalli
authors.affiliation: Kidney Disease Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Kopp
authors.affiliation: Department of Medicine, University of Texas Health Science Center, San Antonio, Texas.
authors.forename: Qian
authors.initials: Q
authors.lastname: Shi
authors.affiliation: Department of Medicine, University of Texas Health Science Center, San Antonio, Texas.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Barnes
authors.affiliation: Department of Medicine, University of Texas Health Science Center, San Antonio, Texas; Audie L. Murphy Memorial Hospital Division, South Texas Veterans Healthcare System, San Antonio, Texas.
authors.forename: Karen
authors.initials: K
authors.lastname: Block
authors.affiliation: Department of Medicine, University of Texas Health Science Center, San Antonio, Texas.
authors.forename: Yves
authors.initials: Y
authors.lastname: Gorin
authors.affiliation: Department of Medicine, University of Texas Health Science Center, San Antonio, Texas; Audie L. Murphy Memorial Hospital Division, South Texas Veterans Healthcare System, San Antonio, Texas.
authors.forename: Hanna E
authors.initials: HE
authors.lastname: Abboud
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D015820:Cadherins / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D058628:Myofibroblasts / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D012263:Ribonucleosides / Q000494:pharmacology; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D015820:Cadherins; D005353:Fibronectins; D012263:Ribonucleosides; D053773:Transforming Growth Factor beta1; D000620:Aminoimidazole Carboxamide; C011651:acadesine; D055372:AMP-Activated Protein Kinases