title: Effect of DNA demethylation in experimental encapsulating peritoneal sclerosis.
abstract: Encapsulating peritoneal sclerosis (EPS) involves excessive peritoneal fibrosis in patients on peritoneal dialysis, eventually leading to visceral constriction and bowel obstruction. Few studies have investigated epigenetic mechanisms relating to EPS. Here we evaluated the therapeutic effects of DNA demethylation in experimental EPS. Experimental EPS was induced by intraperitoneal injection of 0.1% chlorhexidine gluconate (CG) and 15% ethanol in non-uremic male Sprague-Dawley (SD) rats. Rats were divided into three groups: group C (N=5) with saline injection only, group CG (N=7) with EPS induction for 4 weeks, and chlorhexidine gluconate and azacytidine (CGA) treated group (N=7) with EPS induction for 4 weeks and 5'-azacytidine injection for the last 2 weeks. Morphometric analysis of peritoneum and immunohistochemical staining for type 1 collagen and α-smooth muscle actin (α-SMA) were performed. Expressions of transforming growth factor-β (TGF-β), fibroblast-specific protein 1 (FSP1), and DNA methyltransferase 1 (DNMT1) were analyzed by Western blot. Methylation-specific polymerase chain reaction (PCR) for Ras GTPase activating-like protein 1 (RASAL1) was performed with measurement of RASAL1 protein expression. Parietal peritoneal thickness and the number of vessels in omental tissue were significantly decreased in group CGA compared to group CG, as were the expressions of type 1 collagen, α-SMA, TGF-β, and FSP1. DNMT1 was significantly increased in group CG, and reduced in group CGA. RASAL1 hypermethylation was associated with decreased RASAL1 protein expression in group CG, which was reversed in group CGA. DNA demethylation by 5'-azacytidine treatment improved pathologic changes of the peritoneum in experimental EPS, and was associated with reversal of increased DNMT1 expression and RASAL1 hypermethylation.
authors.affiliation: Division of Nephrology and Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Korea.
authors.forename: Kyung-Hoon
authors.initials: KH
authors.lastname: Kim
authors.forename: Hye-Myung
authors.initials: HM
authors.lastname: Ryu
authors.forename: Se-Hyun
authors.initials: SH
authors.lastname: Oh
authors.forename: Eun-Joo
authors.initials: EJ
authors.lastname: Oh
authors.forename: Ji-Sun
authors.initials: JS
authors.lastname: Ahn
authors.forename: Jong-Hak
authors.initials: JH
authors.lastname: Lee
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Choi
authors.forename: Jang-Hee
authors.initials: JH
authors.lastname: Cho
authors.forename: Chan-Duck
authors.initials: CD
authors.lastname: Kim
authors.forename: Yong-Lim
authors.initials: YL
authors.lastname: Kim
authors.forename: Sun-Hee
authors.initials: SH
authors.lastname: Park
mesh_terms: D000818:Animals; D001374:Azacitidine / Q000494:pharmacology*; D002710:Chlorhexidine / Q000031:analogs & derivatives / Q000633:toxicity; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics; D019175:DNA Methylation; D004195:Disease Models, Animal; D000431:Ethanol / Q000633:toxicity; D005786:Gene Expression Regulation; D008297:Male; D010530:Peritoneal Dialysis / Q000009:adverse effects*; D056627:Peritoneal Fibrosis / Q000209:etiology / Q000235:genetics / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020703:ras GTPase-Activating Proteins / Q000235:genetics
chemical_list: D020703:ras GTPase-Activating Proteins; D000431:Ethanol; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619382:Dnmt1 protein, rat; D001374:Azacitidine; C010882:chlorhexidine gluconate; D002710:Chlorhexidine
keywords: DNA demethylation; Encapsulating peritoneal sclerosis; Peritoneal dialysis; Peritoneal fibrosis