Role of the Rho GTPase/Rho kinase signaling pathway in pathogenesis and treatment of glaucoma: Bench to bedside research

Glaucoma is a leading cause of irreversible blindness worldwide. Elevated intraocular pressure (IOP) is considered to be a predominant risk factor for primary open angle glaucoma, the most prevalent form of glaucoma. Although the etiological mechanisms responsible for increased IOP are not completel...

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Bibliographic Details
Published in:Experimental eye research 2017-05, Vol.158, p.23-32
Main Authors: Rao, Ponugoti Vasantha, Pattabiraman, Padmanabhan P., Kopczynski, Casey
Format: Article
Language:English
Subjects:
Animals
Aqueous Humor - metabolism
Aqueous humor outflow
Cytoskeleton
Glaucoma
Glaucoma, Open-Angle - enzymology
Glaucoma, Open-Angle - therapy
Humans
Intraocular pressure
Intraocular Pressure - physiology
Limbus Corneae - metabolism
Point-of-Care Testing
rho GTP-Binding Proteins - physiology
Rho kinase
rho-Associated Kinases - physiology
Signal Transduction - physiology
Trabecular meshwork
Trabecular Meshwork - metabolism
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Summary:Glaucoma is a leading cause of irreversible blindness worldwide. Elevated intraocular pressure (IOP) is considered to be a predominant risk factor for primary open angle glaucoma, the most prevalent form of glaucoma. Although the etiological mechanisms responsible for increased IOP are not completely clear, impairment in aqueous humor (AH) drainage through the conventional or trabecular pathway is recognized to be a primary cause in glaucoma patients. Importantly, lowering of IOP has been demonstrated to reduce progression of vision loss and is a mainstay of treatment for all types of glaucoma. Currently however, there are limited therapeutic options available for lowering IOP especially as it relates to enhancement of AH outflow through the trabecular pathway. Towards addressing this challenge, bench and bedside research conducted over the course of the last decade and a half has identified the significance of inhibiting Rho kinase for lowering IOP. Rho kinase is a downstream effector of Rho GTPase signaling that regulates actomyosin dynamics in numerous cell types. Studies from several laboratories have demonstrated that inhibition of Rho kinase lowers IOP via relaxation of the trabecular meshwork which enhances AH outflow. By contrast, activation of Rho GTPase/Rho kinase signaling in the trabecular outflow pathway increases IOP by altering the contractile, cell adhesive and permeability barrier characteristics of the trabecular meshwork and Schlemm's canal tissues, and by influencing extracellular matrix production and fibrotic activity. This article, written in honor of the late David Epstein, MD, summarizes findings from both basic and clinical studies that have been instrumental for recognition of the importance of the Rho/Rho kinase signaling pathway in regulation of AH outflow, and in the development of Rho kinase inhibitors as promising IOP- lowering agents for glaucoma treatment. •Rho/Rho kinase signaling plays a crucial role in homeostasis of AH outflow and IOP.•Dysregulation of Rho/Rho kinase signaling impairs AH outflow and leads to increased IOP.•Inhibition of Rho/Rho kinase signaling results in an ocular hypotensive response.•Inhibition of Rho/Rho kinase has neuroprotective effects.•Rho kinase inhibition exhibits anti-fibrotic effects in TM and Tenon fibroblasts.
ISSN:0014-4835
1096-0007
DOI:10.1016/j.exer.2016.08.023