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Original Article

Korean J Physiol Pharmacol 2024; 28(4): 345-359

Published online July 1, 2024

Copyright © Korean J Physiol Pharmacol.

Role of TGF-β1/SMADs signalling pathway in resveratrol-induced reduction of extracellular matrix deposition by dexamethasone-treated human trabecular meshwork cells

Amy Suzana Abu Bakar1,2, Norhafiza Razali1,2,*, Renu Agarwal3, Igor Iezhitsa3, Maxim A. Perfilev4, and Pavel M. Vassiliev4

1Department of Pharmacology, Faculty of Medicine, 2Institute of Medical Molecular Biotechnology (IMMB), Universiti Teknologi MARA (UiTM), Sungai Buloh Campus, 47000 Sungai Buloh, Selangor, 3School of Medicine, International Medical University (IMU), Bukit Jalil, 57000 Kuala Lumpur, Malaysia, 4Research Center of Innovative Medicines, Volgograd State Medical University, Pavshikh Bortsov sq. 1, 400131 Volgograd, Russian Federation

Correspondence to:Norhafiza Razali

Received: May 24, 2023; Revised: January 17, 2024; Accepted: February 3, 2024


Deposition of extracellular matrix (ECM) in the trabecular meshwork (TM) increases aqueous humour outflow resistance leading to elevation of intraocular pressure (IOP) in primary open-angle glaucoma, which remains the only modifiable risk factor. Resveratrol has been shown to counteract the steroid-induced increase in IOP and increase the TM expression of ECM proteolytic enzymes; however, its effects on the deposition of ECM components by TM and its associated pathways, such as TGF-β-SMAD signalling remain uncertain. This study, therefore, explored the effects of trans-resveratrol on the expression of ECM components, SMAD signalling molecules, plasminogen activator inhibitor-1 and tissue plasminogen activator in dexamethasone-treated human TM cells (HTMCs). We also studied the nature of molecular interaction of trans -resveratrol with SMAD4 domains using ensemble docking. Treatment of HTMCs with 12.5 µM trans-resveratrol downregulated the dexamethasone-induced increase in collagen, fibronectin and α-smooth muscle actin at gene and protein levels through downregulation of TGF-β1, SMAD4, and upregulation of SMAD7. Downregulation of TGF-β1 signalling by trans-resveratrol could be attributed to its effect on the transcriptional activity due to high affinity for the MH2 domain of SMAD4. These effects may contribute to resveratrol's IOP-lowering properties by reducing ECM deposition and enhancing aqueous humour outflow in the TM.

Keywords: Dexamethasone, Extracellular matrix, Glaucoma, Resveratrol, Trabecular neshwork