Abstract
HL156A is a novel AMP-activated protein kinase (AMPK) activator. We aimed to investigate the protective mechanism of HL156A against peritoneal fibrosis (PF) in in vivo and in vitro models. The rat PF model was induced by daily intraperitoneally injection of chlorhexidine (CHX) solution containing 0.1% CHX gluconate and 15% ethanol for 4 wk. The rats in the treatment group were treated with HL156A (1 mg·kg(-1)·day(-1)). Control rats were injected with vehicle alone. In vitro, cultured rat peritoneal mesothelial cells (RPMCs) were treated with either high glucose (HG; 50 mM), normal glucose (NG; 5 mM), NG+HL156A, or HG+HL156A. HL156A in supplemented rats ameliorated peritoneal calcification, cocoon formation, bowel obstruction, and PF. Immunohistochemistry showed reduced fibronectin accumulation in the peritoneum of HL156A-treated rats compared with those injected with CHX alone. HL156A treatment of RPMCs inhibited HG-induced myofibroblast transdifferentiation and markers of epithelial-mesenchymal transition (EMT). Moreover, HL156A ameliorated HG-induced transforming growth factor-β1, Smad3, Snail, and fibronectin expression in the RPMCs via AMPK upregulation. These results suggest that HL156A exhibits a protective effect in PF progression. Further research is warranted to seek the therapeutic potential of HL156A as an antifibrotic agent in peritoneal dialysis patients.
Keywords:
AMP kinase; HL156A; epithelial-mesenchymal transition (EMT); fibronectin; peritoneal fibrosis.
Copyright © 2016 the American Physiological Society.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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AMP-Activated Protein Kinases / genetics
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AMP-Activated Protein Kinases / metabolism*
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Animals
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Cell Transdifferentiation / drug effects
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Cells, Cultured
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Chlorhexidine / analogs & derivatives
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Cytoprotection
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Disease Models, Animal
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Dose-Response Relationship, Drug
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Enzyme Activation
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Enzyme Activators / chemical synthesis
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Enzyme Activators / pharmacology*
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Epithelial-Mesenchymal Transition / drug effects
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Ethanol
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Fibronectins / genetics
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Fibronectins / metabolism
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Glucose / metabolism
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Guanidines / chemical synthesis
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Guanidines / pharmacology*
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Male
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Myofibroblasts / drug effects
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Myofibroblasts / enzymology
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Myofibroblasts / pathology
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Peritoneal Fibrosis / chemically induced
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Peritoneal Fibrosis / enzymology
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Peritoneal Fibrosis / genetics
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Peritoneal Fibrosis / pathology
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Peritoneal Fibrosis / prevention & control*
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Peritoneum / drug effects*
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Peritoneum / enzymology
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Peritoneum / pathology
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Pyrrolidines / chemical synthesis
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Pyrrolidines / pharmacology*
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RNA Interference
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Rats, Wistar
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Smad3 Protein / genetics
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Smad3 Protein / metabolism
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Snail Family Transcription Factors
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Transfection
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Transforming Growth Factor beta1 / genetics
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Transforming Growth Factor beta1 / metabolism
Substances
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Enzyme Activators
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Fibronectins
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Guanidines
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HL156A
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Pyrrolidines
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Smad3 Protein
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Smad3 protein, rat
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Snai2 protein, rat
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Snail Family Transcription Factors
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Tgfb1 protein, rat
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Transcription Factors
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Transforming Growth Factor beta1
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Ethanol
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Prkaa2 protein, rat
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AMP-Activated Protein Kinases
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Glucose
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chlorhexidine gluconate
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Chlorhexidine