AMP-activated protein kinase inhibits TGF-ß-, angiotensin II-, aldosterone-, high glucose-, and albumin-induced epithelial-mesenchymal transition.
Am J Physiol Renal Physiol
; 304(6): F686-97, 2013 Mar 15.
Article
em En
| MEDLINE
| ID: mdl-23324179
ABSTRACT
The epithelial-mesenchymal transition (EMT) is a novel mechanism that promotes renal fibrosis. Transforming growth factor-ß (TGF-ß), angiotensin II, aldosterone, high glucose, and urinary albumin are well-known causes of EMT and renal fibrosis. We examined whether and how activation of AMP-activated protein kinase (AMPK) suppressed EMT induced by the above agents in tubular epithelial cells. All experiments were performed using HK-2 cells. Protein expression was measured by Western blot analysis. Intracellular reactive oxygen species (ROS) were analyzed by flow cytometry. Exposure of tubular cells to TGF-ß (10 ng/ml), angiotensin II (1 µM), aldosterone (100 nM), high glucose (30 mM), and albumin (5 mg/ml) for 5 days induced EMT, as shown by upregulation of α-smooth muscle actin and downregulation of E-cadherin. ROS and NADPH oxidase 4 (Nox4) expression were increased, and antioxidants such as tiron and N-acetylcysteine inhibited EMT induction. Metformin (the best known clinical activator of AMPK) suppressed EMT induction through inhibition of ROS via induction of heme oxygenase-1 and endogenous antioxidant thioredoxin. An AMPK inhibitor (compound C) and AMPK small interfering RNA blocked the effect of metformin, and another AMPK activator [5-aminoimidazole-4-carboxamide-1ß riboside (AICAR)] exerted the same effects as metformin. In conclusion, AMPK activation might be beneficial in attenuating the tubulointerstitial fibrosis induced by TGF-ß, angiotensin II, aldosterone, high glucose, and urinary albumin.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Tiorredoxinas
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Heme Oxigenase-1
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Proteínas Quinases Ativadas por AMP
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Transição Epitelial-Mesenquimal
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Nefroesclerose
Limite:
Humans
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article