title: AMP-activated protein kinase inhibits TGF-β-, angiotensin II-, aldosterone-, high glucose-, and albumin-induced epithelial-mesenchymal transition.
abstract: The epithelial-mesenchymal transition (EMT) is a novel mechanism that promotes renal fibrosis. Transforming growth factor-β (TGF-β), 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-β (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-1β riboside (AICAR)] exerted the same effects as metformin. In conclusion, AMPK activation might be beneficial in attenuating the tubulointerstitial fibrosis induced by TGF-β, angiotensin II, aldosterone, high glucose, and urinary albumin.
authors: Department of Internal Medicine, Asan Institute for Life Sciences, College of Medicine, University of Ulsan, Seoul, Korea.
authors: Jang Han
authors: JH
authors: Lee
authors: Ji Hyun
authors: JH
authors: Kim
authors: Ja Seon
authors: JS
authors: Kim
authors: Jai Won
authors: JW
authors: Chang
authors: Soon Bae
authors: SB
authors: Kim
authors: Jung Sik
authors: JS
authors: Park
authors: Sang Koo
authors: SK
authors: Lee
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000418:Albumins / Q000378:metabolism; D000450:Aldosterone / Q000378:metabolism; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives; D000804:Angiotensin II / Q000378:metabolism; D002460:Cell Line; D058750:Epithelial-Mesenchymal Transition; D005947:Glucose / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006801:Humans; D008687:Metformin; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000378:metabolism; D009400:Nephrosclerosis / Q000201:enzymology*; D011720:Pyrazoles; D011743:Pyrimidines; D017382:Reactive Oxygen Species / Q000378:metabolism; D012263:Ribonucleosides; D013879:Thioredoxins / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D000418:Albumins; D011720:Pyrazoles; D011743:Pyrimidines; D017382:Reactive Oxygen Species; D012263:Ribonucleosides; D016212:Transforming Growth Factor beta; C516138:dorsomorphin; D000804:Angiotensin II; D000620:Aminoimidazole Carboxamide; D000450:Aldosterone; D013879:Thioredoxins; C011651:acadesine; D008687:Metformin; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498910:NOX4 protein, human; D055372:AMP-Activated Protein Kinases; D005947:Glucose