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

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.

Mechanotransduction and dynamic outflow regulation in trabecular meshwork requires Piezo1 channels

“…Excessive actin polymerization, αSMA-dependent contractility and ECM upregulation represent key harbingers of increased outflow resistance in glaucoma (86,87). Indicating that mechanotransduction contributes to use-dependent formation, alignment and plasticity of cell contacts, we found that exposure to Yoda1 suffices for the upregulation of stress fibers and vinculin-containing puncta.…”

Once-Daily Netarsudil Versus Twice-Daily Timolol in Patients With Elevated Intraocular Pressure: The Randomized Phase 3 ROCKET-4 Study

“…However, this AE may be intolerable to some patients and, in the current study, led to discontinuation in 4.0% of netarsudil-treated patients. Although conjunctival hyperemia is an expected consequence of the known vasodilatory effects of ROCK inhibition, [23][24][25] this ocular AE is not specific to ROCK inhibitors. In a meta-analysis of randomized clinical trials of…”

The future of canine glaucoma therapy

“…Based on this mechanism of action, the drug is expected to be more effective in POAG than PACG. ROCK inhibition reduces cell contractility and cell stiffness, and it decreases expression of fibrosis‐related proteins, resulting in increased trabecular outflow facility . In addition, netarsudil has norepinephrine transporter (NET) inhibitory activity, which may be responsible for the documented reduction of aqueous humor production and decrease in episcleral venous pressure, thereby further contributing to the lowering of IOP .…”

“…ROCK inhibition reduces cell contractility and cell stiffness, and it decreases expression of fibrosis-related proteins, resulting in increased trabecular outflow facility. [29][30][31] In addition, netarsudil has norepinephrine transporter (NET) inhibitory activity, which may be responsible for the documented reduction of aqueous humor production and decrease in episcleral venous pressure, thereby further contributing to the lowering of IOP. 29,32,33 Testing of netarsudil 0.02% ophthalmic solution (corresponding to commercial Rhopressa™) resulted in IOP reduction of ~5 mm Hg in normal Dutch Belted rabbits and Formosan Rock monkeys, but there are no published reports on its effectiveness in dogs.…”