Activation of AMP-activated protein kinase prevents TGF-?1-induced epithelial-mesenchymal transition and myofibroblast activation.
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ABSTRACT: Transforming growth factor (TGF)-? contributes to tubulointerstitial fibrosis. We investigated the mechanism by which TGF-? 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-?1 treatment causes a decrease in AMPK phosphorylation and activation together with increased fibronectin and ?-smooth muscle actin expression and decreased in E-cadherin. TGF-?1 causes similar changes in interstitial fibroblasts. Activation of AMPK with 5-aminoimidazole-4-carboxamide 1-?-d-ribofuranoside, metformin, or overexpression of constitutively active AMPK markedly attenuated TGF-?1 functions. Conversely, inhibition of AMPK with adenine 9-?-d-arabinofuranoside or siRNA-mediated knockdown of AMPK (official name PRKAA1) mimicked the effect of TGF-?1 and enhanced basal and TGF-?1-induced phenotypic changes. Importantly, we found that tuberin contributed to the protective effects of AMPK and that TGF-?1 promoted cell injury by blocking AMPK-mediated tuberin phosphorylation and activation. In the kidney cortex of TGF-? 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-? exerts its profibrotic action in vitro and in vivo via inactivation of AMPK. AMPK and tuberin activation prevent tubulointerstitial injury induced by TGF-?. Activators of AMPK provide potential therapeutic strategy to prevent kidney fibrosis and progressive kidney disease.
SUBMITTER: Thakur S
PROVIDER: S-EPMC4530134 | biostudies-literature | 2015 Aug
REPOSITORIES: biostudies-literature
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