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5-Aza-2′-deoxycytidine induces human Tenon's capsule fibroblasts differentiation and fibrosis by up-regulating TGF-β type I receptor

5-Aza-2′-deoxycytidine induces human Tenon's capsule fibroblasts differentiation and fibrosis by up-regulating TGF-β type I receptor

Authors :
Wen Ye
Li Sun
Shuhao Fu
Huimin Shi
Yiqin Xiao
Kang Xu
Xiaoyan Zhang
Source :
Experimental Eye Research. 165:47-58
Publication Year :
2017
Publisher :
Elsevier BV, 2017.

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)-β1 signaling. TGF-β1 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-β1-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-β1. 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-β type I receptor (TGFβRI). Furthermore, the effects of 5-Aza-dc on DNMT activity suppression, cell migration, and fibrosis were all reversed by a TGFβRI inhibitor- SB-431542. Meanwhile, knockdown of DNMT1 upregulated TGFβRI 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 TGFβRI. DNA methylation status plays an important role in subconjunctival wound healing.

Details

ISSN :
00144835
Volume :
165
Database :
OpenAIRE
Journal :
Experimental Eye Research
Accession number :
edsair.doi.dedup.....e2a441c5c8b42f4f8927da0e92e2dabe
Full Text :
https://doi.org/10.1016/j.exer.2017.09.004