Metformin protects trabecular meshwork against oxidative injury via activating integrin/ROCK signals
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Curated by eLife
eLife assessment
This manuscript proposes that metformin protects against elevated intraocular pressure and oxidative injury by regulating cytoskeleton remodeling through the integrin/ROCK pathway, thus providing a new direction for further exploration toward the treatment of primary open-angle glaucoma as well as investigation of oxidative injury in multiple settings.
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- Pharmacology and Toxicology (eLife)
Abstract
This study aimed to investigate the protective effect of metformin on trabecular meshwork (TM) and explore its molecular mechanisms in vivo and in vitro. Ocular hypertension (OHT) mouse models were induced with dexamethasone and further treated with metformin to determine the intraocular pressure (IOP)-lowering effect. Cultured human TM cells (HTMCs) were pre-stimulated with tert-butyl hydroperoxide (tBHP) to induce oxidative damage and then supplemented with metformin for another 24 hr. The expression of fibrotic markers and integrin/Rho-associated kinase (ROCK) signals, including α-smooth muscle actin (α-SMA), transforming growth factor-β (TGF-β), fibronectin, integrin beta 1, ROCK 1/2, AMP-activated protein kinase, myosin light chain 1, and F-actin were determined by western blotting and immunofluorescence. Reactive oxygen species (ROS) content was analysed using flow cytometry. Transmission electron microscopy was performed to observe microfilaments in HTMCs. It showed that metformin administration reduced the elevated IOP and alleviated the fibrotic activity of aqueous humour outflow in OHT models. Additionally, metformin rearranged the disordered cytoskeleton in the TM both in vivo and in vitro and significantly inhibited ROS production and activated integrin/ROCK signalling induced by tBHP in HTMCs. These results indicated that metformin reduced the elevated IOP in steroid-induced OHT mouse models and exerted its protective effects against oxidative injury by regulating cytoskeleton remodelling through the integrin/ROCK pathway. This study provides new insights into metformin use and preclinical evidence for the potential treatment of primary open-angle glaucoma.
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eLife assessment
This manuscript proposes that metformin protects against elevated intraocular pressure and oxidative injury by regulating cytoskeleton remodeling through the integrin/ROCK pathway, thus providing a new direction for further exploration toward the treatment of primary open-angle glaucoma as well as investigation of oxidative injury in multiple settings.
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Reviewer #1 (Public Review):
The authors show that metformin reduced the elevated intraocular pressure in mice with steroid-induced ocular hypertension and attenuated damage to the cytoskeleton of the ocular trabecular meshwork. In human trabecular meshwork cells, the authors showed that the protective effects of metformin against oxidative injury were exerted by regulating cytoskeleton remodeling through integrin/ROCK signals.
Strengths of the paper include the rigorous methodology and support of the data for the conclusions. The work has the potential to advance glaucoma research but also the use of metformin for reversing other states of oxidative injury, such as fundamental aging mechanisms, in multiple tissues.
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Reviewer #2 (Public Review):
What the authors were trying to explore is very interesting with translational potential toward glaucoma treatment. They used a topical dexamethasone (dex) induced mouse model showing ocular hypertension and a culture model using human TM cells treated with tBHP to induce TM oxidative stress. Their results suggested that metformin protected TM cells from cytoskeletal destruction by enhancing the integrin/ROCK pathway and alleviated elevated IOP in the mouse model. However, the provided simulative results were vague and the research needs extra experimental data to support its conclusion.
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