Abstract
Recent evidence suggests that chloride channels are critical for cell proliferation, migration, and differentiation. We examined the effects of transforming growth factor (TGF)-β1 on chloride channel expression and associations with human conjunctival fibroblast (HConF) biology. To investigate the potential role of chloride channel (CLC)-2 in migration, transition to myofibroblasts and extracellular matrix (ECM) synthesis of HconF, a small interfering RNA (siRNA) approach was applied. TGF-β1-induced migration and transition of fibroblasts to myofibroblasts characterized by α-smooth muscle actin (α-SMA) expression, supported by increased endogenous expression of CLC-2 protein and mRNA transcripts. ECM (collagen I and fibronectin) synthesis in HConF was enhanced by TGF-β1. CLC-2 siRNA treatment reduced TGF-β1-induced cell migration, transition of fibroblasts to myofibroblasts, and ECM synthesis of HConF. CLC-2 siRNA treatment in the presence of TGF-β1 inhibited phosphorylation of PI3K and Akt in HConF. These findings demonstrate that CLC-2 chloride channels are important for TGF-β1-induced migration, differentiation, and ECM synthesis via PI3K/Akt signaling in HConF.
Highlights
Postoperative scarring is the most common reason for failure of glaucoma filtering surgery
ClC-3 knockdown in the presence of transforming growth factor (TGF)-β1 in human corneal keratocytes and human fetal lung fibroblasts was previously shown to reduce α-smooth muscle actin (α-SMA) protein expression, whereas α-SMA protein expression was significantly increased by ClC-3 overexpression in the absence of TGF-β1; these findings suggest that ClC-3 is involved in the transition of fibroblasts into myofibroblasts [13]
The present study provides the first report on the involvement of chloride channel (CLC)-2 channels in TGF-β1-associated fibroblast differentiation, migration, and extracellular matrix (ECM) synthesis in human conjunctival fibroblast (HConF)
Summary
Postoperative scarring is the most common reason for failure of glaucoma filtering surgery. Transforming growth factor β (TGF-β) is recognized as a major driver of postoperative scarring after glaucoma surgery [4,5], that increases collagen deposition, inhibits collagen degradation, and promotes transformation of fibroblast into myofibroblasts and migration of myofibroblasts [6,7]. Chloride channe (CLC)-3 overexpression was previously shown to promote fibroblast-to-myofibroblast transition reflected by increased α-smooth muscle actin (α-SMA). T[h14e] rfooulendofthcahtlRoNriAdiekcnhoacknonuet losfitnhehCuLmC-a2ngcenoenjiunhnibcittievdahl ifighbrgolubcloasset-sinadfutceerdglaucoma filtering sumriggreartyionaroef lriamt ikteerdat.inTochyetesprveiaseinnhtibsittuiodnyoaf pppholisepdhaCtidLyCl--In2oksintool c3k-kdinoawsen(PinI3Kh)usmigananlincgo.njunctival Together, these studies have provided direct evidence of the physiological relationship between fibroblastsch(lHoricdoencFh)antnoelsdaentderfmibrionbelaswt-tho-emthyoefribCroLblCas-t2trapnasrdtiifcfeirpeanttieastioinninthaeddfiitibornotbolapsrotl-itfoer-amtioyno, fibroblast transition,mmigrigatrioanti, oanndofECmMyopfirobdruoctbiolansitns,maanndy EceCll Mtypseys.nHthoewseivseirn, stuhdeieps roensetnheceroolef oTfGcFhloβri1deto explore effective mcheathnnoedlssintohupmreavnecnont jsucnactrirvianlgfibirnobgllaastuscaoftmeraglfiaultceorminagfilsteurirnggesruyr.gery are limited. 2. ResultsCLC-2 participates in the fibroblast-to-myofibroblast transition, migration of myofibroblasts, and ECM synthesis in the presence of TGF β1 to explore effective methods to prevent scarring in. A-NC: mutant CTGLFC--β21siniRANNAO;V*Ap).< 0.05, ** p < 0.01 vs. control; # p < 0.05 vs. TGF-β1 in ANOVA)
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