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bioRxiv · 10.1101/2022.06.30.498232

Metformin protects trabecular meshwork against oxidative injury via activating integrin/ROCK signals

Xu, L.·Zhang, X.·Zhao, Y.·Cao, Y.·Liang, Y.
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Abstract

BackgroundThis study aimed to investigate the protective effect of metformin on the trabecular meshwork (TM) and explore its molecular mechanisms in vivo and in vitro. MethodsOcular hypertension (OHT) mouse models were induced with dexamethasone (DEX) and further treated with metformin to determine its IOP lowering effect. Cultured human TM cells (HTMC) were pre-stimulated with tert-butyl hydroperoxide (tBHP) to induce oxidative damage and then supplemented with metformin for another 24 h. The expression of fibrotic markers and integrin/ROCK signals, including -SMA, TGF-{beta}, fibronectin, F-actin, integrin beta 1, Rho-associated kinase (ROCK)1/2, AMP-activated protein kinase (AMPK), myosin light chain 1 (MLC 1), and F-actin were determined by western blotting (WB) and immunofluorescence (IF). Reactive oxygen species (ROS) content was analysed using flow cytometry (FCM). ResultsAdministration of metformin 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. Furthermore, metformin significantly inhibited ROS production and activated integrin/ROCK signalling induced by tBHP in HTMC. ConclusionMetformin 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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Xu, L., Zhang, X., Zhao, Y., Cao, Y., Liang, Y.. 2022-07-03. Metformin protects trabecular meshwork against oxidative injury via activating integrin/ROCK signals. https://doi.org/10.1101/2022.06.30.498232

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