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

• Published in: Korean Journal of Physiology and Pharmacology
• Main Author: Bakar A.S.A.; Razali N.; Agarwal R.; Iezhitsa I.; Perfilev M.A.; Vassiliev P.M.
• Format: Article
• Language: English
• Published: Korean Physiological Soc. and Korean Soc. of Pharmacology 2024
• Online Access: https://www.scopus.com/inward/record.uri?eid=2-s2.0-85198983678&doi=10.4196%2fkjpp.2024.28.4.345&partnerID=40&md5=69978ed7e604b9f53154f00092f8906f

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. © 2024 Korean Physiological Soc. and Korean Soc. of Pharmacology. All rights reserved.