title: HL156A, a novel AMP-activated protein kinase activator, is protective against peritoneal fibrosis in an in vivo and in vitro model of peritoneal fibrosis.
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.
authors.affiliation: Institute of Biomedical Research, Seoul National University Hospital, Seoul, Korea;
authors.forename: Kyung Don
authors.initials: KD
authors.lastname: Ju
authors.affiliation: Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea;
authors.forename: Hyo Jin
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Institute of Biomedical Research, Seoul National University Hospital, Seoul, Korea;
authors.forename: Bodokhsuren
authors.initials: B
authors.lastname: Tsogbadrakh
authors.affiliation: Institute of Biomedical Research, Seoul National University Hospital, Seoul, Korea;
authors.forename: Jinho
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea;
authors.forename: Hyunjin
authors.initials: H
authors.lastname: Ryu
authors.affiliation: Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea;
authors.forename: Eun Jin
authors.initials: EJ
authors.lastname: Cho
authors.affiliation: Department of Internal Medicine, Eulji University, Seoul, Korea; and.
authors.forename: Young-Hwan
authors.initials: YH
authors.lastname: Hwang
authors.affiliation: Nephrology Clinic, National Cancer Center, Goyang, Korea.
authors.forename: Kiwon
authors.initials: K
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea; Institute of Transplantation Research, Seoul National University Hospital, Seoul, Korea;
authors.forename: Jaeseok
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea; Institute of Transplantation Research, Seoul National University Hospital, Seoul, Korea;
authors.forename: Curie
authors.initials: C
authors.lastname: Ahn
authors.affiliation: Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea; khoh@snu.ac.kr.
authors.forename: Kook-Hwan
authors.initials: KH
authors.lastname: Oh
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D054338:Cell Transdifferentiation / Q000187:drug effects; D002478:Cells, Cultured; D002710:Chlorhexidine / Q000031:analogs & derivatives; D019610:Cytoprotection; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000138:chemical synthesis / Q000494:pharmacology*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D000431:Ethanol; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006146:Guanidines / Q000138:chemical synthesis / Q000494:pharmacology*; D008297:Male; D058628:Myofibroblasts / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D056627:Peritoneal Fibrosis / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D010537:Peritoneum / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000494:pharmacology*; D034622:RNA Interference; D017208:Rats, Wistar; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism
chemical_list: D020536:Enzyme Activators; D005353:Fibronectins; D006146:Guanidines; C000609148:HL156A; D011759:Pyrrolidines; D051900:Smad3 Protein; C497787:Smad3 protein, rat; C000604450:Snai2 protein, rat; D000071250:Snail Family Transcription Factors; C508962:Tgfb1 protein, rat; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; D000431:Ethanol; C543928:Prkaa2 protein, rat; D055372:AMP-Activated Protein Kinases; D005947:Glucose; C010882:chlorhexidine gluconate; D002710:Chlorhexidine
keywords: AMP kinase; HL156A; epithelial-mesenchymal transition (EMT); fibronectin; peritoneal fibrosis