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Exp Eye Res. 2017 May;158:23-32. doi: 10.1016/j.exer.2016.08.023. Epub 2016 Sep 1.

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

Author information

1
Department of Ophthalmology, Duke University School of Medicine, Durham, NC, USA; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA. Electronic address: p.rao@dm.duke.edu.
2
Department of Ophthalmology, Duke University School of Medicine, Durham, NC, USA.
3
Aerie Pharmaceuticals, Durham, NC, USA.

Abstract

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.

KEYWORDS:

Aqueous humor outflow; Cytoskeleton; Glaucoma; Intraocular pressure; Rho kinase; Trabecular meshwork

PMID:
27593914
PMCID:
PMC5332476
DOI:
10.1016/j.exer.2016.08.023
[Indexed for MEDLINE]
Free PMC Article

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