Activation of AMP-Activated Protein Kinase Prevents TGF-β1-Induced Epithelial-Mesenchymal Transition and Myofibroblast Activation

Sachin Thakur, Suryavathi Viswanadhapalli, Jeffrey B. Kopp, Qian Shi, Jeffrey L. Barnes, Karen Block, Yves Gorin, Hanna E. Abboud

Research output: Contribution to journalArticlepeer-review

43 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2168-2180
Number of pages13
JournalAmerican Journal of Pathology
Volume185
Issue number8
DOIs
StatePublished - Aug 1 2015

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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