Suppressive effect of AMP-activated protein kinase on the epithelial-mesenchymal transition in retinal pigment epithelial cells

Ryo Matoba, Yuki Morizane, Yusuke Shiode, Masayuki Hirano, Shinichiro Doi, Shinji Toshima, Ryoichi Araki, Mika Hosogi, Tomoko Yonezawa, Fumio Shiraga

Research output: Contribution to journalArticle

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Abstract

The epithelial-mesenchymal transition (EMT) in retinal pigment epithelial (RPE) cells plays a central role in the development of proliferative vitreoretinopathy (PVR). The purpose of this study was to investigate the effect of AMP-activated protein kinase (AMPK), a key regulator of energy homeostasis, on the EMT in RPE cells. In this study, EMT-associated formation of cellular aggregates was induced by co-stimulation of cultured ARPE-19 cells with tumor necrosis factor (TNF)-α (10 ng/ml) and transforming growth factor (TGF)-β2 (5 ng/ml). 5-Aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR), a potent activator of AMPK, significantly suppressed TNF-α and TGF-β2-induced cellular aggregate formation (p < 0.01). Dipyridamole almost completely reversed the suppressive effect of AICAR, whereas 5’-amino-5’-deoxyadenosine restored aggregate formation by approximately 50%. AICAR suppressed the downregulation of E-cadherin and the upregulation of fibronectin and α-smooth muscle actin by TNF-α and TGF-β2. The levels of matrix metalloproteinase (MMP)-2, MMP-9, interleukin-6, and vascular endothelial growth factor were significantly decreased by AICAR. Activation of the mitogen-activated protein kinase and mammalian target of rapamycin pathways, but not the Smad pathway, was inhibited by AICAR. These findings indicate that AICAR suppresses the EMT in RPE cells at least partially via activation of AMPK. AMPK is a potential target molecule for the prevention and treatment of PVR, so AICAR may be a promising candidate for PVR therapy.

Original languageEnglish
Article numbere0181481
JournalPLoS One
Volume12
Issue number7
DOIs
Publication statusPublished - Jul 1 2017

Fingerprint

Aminoimidazole Carboxamide
AMP-activated protein kinase
AMP-Activated Protein Kinases
Retinal Pigments
Epithelial-Mesenchymal Transition
transforming growth factors
tumor necrosis factors
epithelial cells
protein aggregates
Epithelial Cells
pigments
Proliferative Vitreoretinopathy
Transforming Growth Factors
dipyridamole
Tumor Necrosis Factor-alpha
gelatinase A
gelatinase B
vascular endothelial growth factors
cadherins
fibronectins

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Suppressive effect of AMP-activated protein kinase on the epithelial-mesenchymal transition in retinal pigment epithelial cells. / Matoba, Ryo; Morizane, Yuki; Shiode, Yusuke; Hirano, Masayuki; Doi, Shinichiro; Toshima, Shinji; Araki, Ryoichi; Hosogi, Mika; Yonezawa, Tomoko; Shiraga, Fumio.

In: PLoS One, Vol. 12, No. 7, e0181481, 01.07.2017.

Research output: Contribution to journalArticle

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