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Open AccessArticle

Nox4 Facilitates TGFβ1-Induced Fibrotic Response in Human Tenon’s Fibroblasts and Promotes Wound Collagen Accumulation in Murine Model of Glaucoma Filtration Surgery

1
Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Victoria 3002, Australia
2
Department of Medicine, University of Melbourne, Melbourne 3010, Victoria, Australia
3
Centre for Vision Research, Duke-NUS, Singapore 169856, Singapore
4
Singapore Eye Research Institute/ Singapore National Eye Centre (SERI/ SNEC), Singapore 169856, Singapore
5
Department of Ophthalmology, University of Melbourne, Melbourne 3010, Victoria, Australia
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Deceased 7 October 2017.
Antioxidants 2020, 9(11), 1126; https://doi.org/10.3390/antiox9111126
Received: 19 September 2020 / Revised: 25 October 2020 / Accepted: 26 October 2020 / Published: 13 November 2020
Collagen accumulation in sub-conjunctival tissue at the surgical wound is one of the major complications associated with glaucoma filtration surgery (GFS). This process often leads to unwanted fibrotic scar formation at the lesion site and dysfunction of tissues. Previously, we demonstrated that NADPH oxidase 4 (Nox4) is implicated in transforming growth factor-beta (TGFβ)-induced collagen production in ocular fibroblasts and scarring responses in a mouse model of corneal injury. Here, we propose that Nox4 is an important facilitator of TGFβ-induced responses. We tested this hypothesis in human Tenon’s fibroblasts (HTF) and also assessed a role of Nox4 in an experimental mouse model of GFS. TGFβ1 induced Nox4 mRNA expression but downregulated Nox5 in HTF. Targeting Nox4 gene expression with an adenovirus carrying a Nox4 small interfering RNA (siRNA) (Ad-Nox4i) or removal of hydrogen peroxide (H2O2) with EUK-134 (25 μM) in HTFs significantly reduced TGFβ1-induced Nox4 expression, H2O2 production, and collagen synthesis (p < 0.05, n = 3–6). SIS3 (5 μM) that prevents Smad3 phosphorylation is found to suppress TGFβ1-induced collagen production in HTFs. Furthermore, Ad-Nox4i and EUK-134 both abolished TGFβ1-stimulated proliferation of HTFs. We also compared collagen deposition at the wound arising from GFS between wildtype (WT) and Nox4 knockout (KO) mice. Both collagen deposition and fibrovascularization at the wound were significantly decreased in Nox4 KO mice at 14 days after GFS. Our results provide comprehensive evidence that Nox4 is an important mediator for TGFβ1-induced responses in HTFs and collagen deposition in surgical wound following GFS in mice. As such, pharmacological inhibition of Nox4 would be a viable therapeutic strategy for the control of scarring after glaucoma surgery. View Full-Text
Keywords: collagen; glaucoma filtration surgery; NADPH Oxidase; transforming growth factor-beta; reactive oxygen species collagen; glaucoma filtration surgery; NADPH Oxidase; transforming growth factor-beta; reactive oxygen species
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MDPI and ACS Style

Shah, M.H.; Chan, E.C.; Van Bergen, N.J.; Pandav, S.S.; Ng, S.; Crowston, J.G.; Peshavariya, H.M. Nox4 Facilitates TGFβ1-Induced Fibrotic Response in Human Tenon’s Fibroblasts and Promotes Wound Collagen Accumulation in Murine Model of Glaucoma Filtration Surgery. Antioxidants 2020, 9, 1126. https://doi.org/10.3390/antiox9111126

AMA Style

Shah MH, Chan EC, Van Bergen NJ, Pandav SS, Ng S, Crowston JG, Peshavariya HM. Nox4 Facilitates TGFβ1-Induced Fibrotic Response in Human Tenon’s Fibroblasts and Promotes Wound Collagen Accumulation in Murine Model of Glaucoma Filtration Surgery. Antioxidants. 2020; 9(11):1126. https://doi.org/10.3390/antiox9111126

Chicago/Turabian Style

Shah, Manisha H.; Chan, Elsa C.; Van Bergen, Nicole J.; Pandav, Surinder S.; Ng, Sze; Crowston, Jonathan G.; Peshavariya, Hitesh M. 2020. "Nox4 Facilitates TGFβ1-Induced Fibrotic Response in Human Tenon’s Fibroblasts and Promotes Wound Collagen Accumulation in Murine Model of Glaucoma Filtration Surgery" Antioxidants 9, no. 11: 1126. https://doi.org/10.3390/antiox9111126

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