Downregulation of COL12A1 and COL13A1 by a selective EP2 receptor agonist, omidenepag, in human trabecular meshwork cells

Abstract

Omidenepag isopropyl (OMDI) is an intraocular pressure (IOP)-lowering drug used to treat glaucoma. The active form of OMDI, omidenepag (OMD), lowers elevated IOP, the main risk factor for glaucoma, by increasing the aqueous humor outflow; however, a detailed understanding of this mechanism is lacking. To clarify the IOP-lowering mechanism of OMDI, the effects of OMD on the mRNA expression of the extracellular matrix, matrix metalloproteinases (MMPs), and tissue inhibitors of metalloproteinases (TIMPs) were evaluated in human trabecular meshwork cells. Under 2D culture conditions, the mRNA expression ofFN1,COL1A1,COL1A2,COL12A1, andCOL13A1decreased in a concentration-dependent manner after 6 or 24 h treatment with 10 nM, 100 nM, and 1 μM OMD, while that ofCOL18A1decreased after 6 h treatment with 1 μM OMD. Significant changes in expression were observed for many MMP and TIMP genes. Under 3D culture conditions, the extracellular matrix-related genesCOL12A1andCOL13A1were downregulated by OMD treatment at all three concentrations. Under both 2D and 3D culture conditions,COL12A1andCOL13A1were downregulated following OMD treatment. Reduction in the extracellular matrix contributes to the decrease in outflow resistance, suggesting that the downregulation of the two related genes may be one of the factors influencing the IOP-lowering effect of OMDI. Our findings provide insights for the use of OMDI in clinical practice.