5-Aza-2'-deoxycytidine induces human Tenon's capsule fibroblasts differentiation and fibrosis by up-regulating TGF-ß type I receptor.
Exp Eye Res
; 165: 47-58, 2017 12.
Article
em En
| MEDLINE
| ID: mdl-28893564
ABSTRACT
The principle reason of high failure rate of glaucoma filtration surgery is the loss of filtration function caused by postoperative scar formation. We investigated the effects of 5-aza-2'-deoxycytidine (5-Aza-dc), a DNA methyltransferases inhibitor, on human Tenon's capsule fibroblasts (HTFs) differentiation and fibrosis and its mechanism of action, especially in relation to transforming growth factor (TGF)-ß1 signaling. TGF-ß1 was used to induce differentiation of cultured HTFs. 5-Aza-dc suppressed DNA methyltransferases (DNMTs) activity 6 h after treatment with a course corresponding to that of TGF-ß1-induced reduction of DNMT activity without affecting cell viability as measured by Cell Counting Kit-8 assay. 5-Aza-dc also reduced DNMT1 and DNMT3a protein expression from 24 to 48 h. HTFs migration evaluated by scratch-wound assay were significantly increased 24 h after 5-Aza-dc treatment, a time course similar to that of TGF-ß1. Treatment with 5-Aza-dc significantly increased the mRNA and protein levels of α-smooth muscle actin (α-SMA), collagen-1A1 (Col1A1), fibronectin (FN) and TGF-ß type I receptor (TGFßRI). Furthermore, the effects of 5-Aza-dc on DNMT activity suppression, cell migration, and fibrosis were all reversed by a TGFßRI inhibitor- SB-431542. Meanwhile, knockdown of DNMT1 upregulated TGFßRI expression and had the same fibrosis-inducing effect in HTFs, which was also inhibited by SB-431542. Thus, the results indicate that DNA hypomethylation induces HTFs differentiation and fibrosis through up-regulation of TGFßRI. DNA methylation status plays an important role in subconjunctival wound healing.
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Bases de dados:
MEDLINE
Assunto principal:
Azacitidina
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Fibrose
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Inibidores Enzimáticos
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Cápsula de Tenon
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Fibroblastos
Limite:
Adult
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Exp Eye Res
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
China