| First Author | Thakur S | Year | 2015 |
| Journal | Am J Pathol | Volume | 185 |
| Issue | 8 | Pages | 2168-80 |
| PubMed ID | 26071397 | Mgi Jnum | J:225649 |
| Mgi Id | MGI:5693987 | Doi | 10.1016/j.ajpath.2015.04.014 |
| Citation | Thakur S, et al. (2015) Activation of AMP-activated protein kinase prevents TGF-beta1-induced epithelial-mesenchymal transition and myofibroblast activation. Am J Pathol 185(8):2168-80 |
| abstractText | Transforming growth factor (TGF)-beta contributes to tubulointerstitial fibrosis. We investigated the mechanism by which TGF-beta 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-beta1 treatment causes a decrease in AMPK phosphorylation and activation together with increased fibronectin and alpha-smooth muscle actin expression and decreased in E-cadherin. TGF-beta1 causes similar changes in interstitial fibroblasts. Activation of AMPK with 5-aminoimidazole-4-carboxamide 1-beta-d-ribofuranoside, metformin, or overexpression of constitutively active AMPK markedly attenuated TGF-beta1 functions. Conversely, inhibition of AMPK with adenine 9-beta-d-arabinofuranoside or siRNA-mediated knockdown of AMPK (official name PRKAA1) mimicked the effect of TGF-beta1 and enhanced basal and TGF-beta1-induced phenotypic changes. Importantly, we found that tuberin contributed to the protective effects of AMPK and that TGF-beta1 promoted cell injury by blocking AMPK-mediated tuberin phosphorylation and activation. In the kidney cortex of TGF-beta 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-beta exerts its profibrotic action in vitro and in vivo via inactivation of AMPK. AMPK and tuberin activation prevent tubulointerstitial injury induced by TGF-beta. Activators of AMPK provide potential therapeutic strategy to prevent kidney fibrosis and progressive kidney disease. |
