Effects of selective EP2 receptor agonist, omidenepag, on trabecular meshwork cells, Schlemm\u2019s canal endothelial cells and ciliary muscle contraction

Nozomi Igarashi,Rei Sakata,Makoto Aihara,Reiko Yamagishi,Megumi Honjo,Natsuko Nakamura

doi:10.1038/s41598-021-95768-z

Abstract

This study investigated the effects of omidenepag (OMD), a novel selective EP2 receptor agonist, on human trabecular meshwork (HTM) cells, monkey Schlemm’s canal endothelial (SCE) cells, and porcine ciliary muscle (CM) to clarify the mechanism of intraocular pressure (IOP) reduction involving conventional outflow pathway. In HTM and SCE cells, the effects of OMD on transforming growth factor-β2 (TGF-β2)-induced changes were examined. The expression of actin cytoskeleton and extracellular matrix (ECM) proteins, myosin light chain (MLC) phosphorylation in HTM cells were evaluated using real-time quantitative PCR, immunocytochemistry, and western blotting. The expression of barrier-related proteins, ZO-1 and β-catenin, and permeability of SCE cells were evaluated using immunocytochemistry and transendothelial electrical resistance. The CM contraction was determined by contractibility assay. OMD significantly inhibited expression of TGF-β2 induced mRNA, protein, and MLC-phosphorylation on cytoskeletal and ECM remodeling in the HTM dose dependently. In SCE cells, OMD suppressed TGF-β2-induced expression of the barrier-related proteins and decreased SCE monolayer permeability. OMD at 3 µM significantly inhibited CM contraction, however, the effect was not significant at lower concentrations. IOP lowering effect of OMD through conventional outflow pathway is exerted by increasing outflow facilities with the modulation of TM cell fibrosis and SCE cell permeability.

Highlights

Glaucoma is a progressive optic neuropathy characterized by the selective retinal ganglion cell death, and elevated intraocular pressure (IOP) is the most critical risk factor in all glaucoma subtypes[1,2]
We evaluated the effects of OMD on human trabecular meshwork (TM) (HTM) cells, monkey s canal endothelial (SCE) cells and porcine ciliary muscle (CM) to investigate the IOP lowering mechanism of OMD in conventional outflow
We investigated the effects of OMD on transforming growth factor-β2 (TGF-β2)-induced fibrogenic changes in HTM cells

Summary

Introduction

Glaucoma is a progressive optic neuropathy characterized by the selective retinal ganglion cell death, and elevated intraocular pressure (IOP) is the most critical risk factor in all glaucoma subtypes[1,2]. There are two types of outflow routes: the conventional pathway and the uveoscleral pathway[3]. The main cause of elevated IOP in primary open angle glaucoma (POAG), the most common glaucoma subtype, is increased outflow resistance in the conventional outflow pathway[4]. IOP reduction is currently the only reliable, evidence-based treatment of glaucoma, with pharmacological agents used as the first-line of therapy in most types of glaucoma, including prostaglandin (PG) analogs. There is a great clinical need for a first line drug treatments with potent IOP lowering effects that do not cause the adverse reactions associated with thePGF2α analogue. We evaluated the effects of OMD on human TM (HTM) cells, monkey SCE cells and porcine CM to investigate the IOP lowering mechanism of OMD in conventional outflow

Methods

Results

Conclusion