title: Histone acetyltransferase inhibitor C646 reverses epithelial to mesenchymal transition of human peritoneal mesothelial cells via blocking TGF-β1/Smad3 signaling pathway in vitro.
abstract: Peritoneal fibrosis resulting from long-term peritoneal dialysis is a major cause of failure of peritoneal ultrafiltration function and main reason of dropout from peritoneal dialysis. Epithelial-mesenchymal transition (EMT) of peritoneal mesochelial cells (HPMCs) is a major contributor of peritoneal fibrosis. Recently, the association between histone acetylation and kinds of fibrosis including liver, lung and kidney fibrosis is well established. Thus, in this study we tried to profile whether histone acetylation is also operates EMT process in HPMCs and what's the regulatory mechanism. We established an EMT model of HPMCs through high glucose treatment. And hyperacetylation of H3 histone was found using western blot in EMT model. After treated with C646, a histone acetyltransferase (HAT) inhibitor, high glucose-induced EMT in HPMCs was counteracted. To further understand the molecular mechanism of C646 rescues high glucose-induced EMT, CHIP-qPCRwas used to examine the modulation of histone H3 acetylation at promoters of series signaling target genes. We found that the H3 acetylation level at TGF-β1 gene promoter was down-regulation by C646 treatment. Moreover, we also found that TGF-β1/Smad3 signaling was blocked. Hence, our results suggest that histone H3 acetylation activated TGF-β1/Smad3 signaling during EMT of HPMCs, and C646 can rescue the mesenchymal phenotype transition. These findings may provide a novel pathogenic mechanism and therapeutic target for peritoneal fibrosis.
authors.affiliation: Department of Nephrology, Hunan Provincial People's Hospital Changsha 41005, China.
authors.forename: Yiya
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Nephrology, Hunan Provincial People's Hospital Changsha 41005, China.
authors.forename: Kanghan
authors.initials: K
authors.lastname: Liu
authors.affiliation: Department of Nephrology, Hunan Provincial People's Hospital Changsha 41005, China.
authors.forename: Yumei
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Department of Nephrology, Hunan Provincial People's Hospital Changsha 41005, China.
authors.forename: Yinyin
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Nephrology, Hunan Provincial People's Hospital Changsha 41005, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Nephrology, Hunan Provincial People's Hospital Changsha 41005, China.
authors.forename: Yuting
authors.initials: Y
authors.lastname: Gong
mesh_terms: D000107:Acetylation; D001565:Benzoates / Q000494:pharmacology*; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D004848:Epithelium / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D005355:Fibrosis; D005947:Glucose / Q000633:toxicity; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D009578:Nitrobenzenes; D056627:Peritoneal Fibrosis / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D010537:Peritoneum / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D010641:Phenotype; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational; D011720:Pyrazoles / Q000494:pharmacology*; D047069:Pyrazolones; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D051900:Smad3 Protein / Q000378:metabolism*; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*
chemical_list: C584509:4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid; D001565:Benzoates; D004791:Enzyme Inhibitors; D006657:Histones; D009578:Nitrobenzenes; D011720:Pyrazoles; D047069:Pyrazolones; C497790:SMAD3 protein, human; D051900:Smad3 Protein; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; D051548:Histone Acetyltransferases; D005947:Glucose
keywords: Peritoneal fibrosis; TGF-β1/Smad3 signaling; epithelial-mesenchymal transition; histone acetylation; histone acetyltransferase (HAT) inhibitor