sGCα1-Deficient Mice: A Novel Murine Model Of Spontaneous Primary Open Angle Glaucoma

Abstract

Purpose: : Primary open angle glaucoma (POAG) is a common, progressive eye disease that leads to blindness due to the loss of retinal ganglion cells (RGCs) and degeneration of the optic nerve. Elevated intraocular pressure (IOP) is an important risk factor for glaucoma. However, the exact molecular mechanisms that trigger increased IOP and glaucomatous optic neuropathy are incompletely understood. While a few spontaneous murine models of glaucoma exist, none are models of POAG. Impaired nitric oxide (NO)/cGMP signaling has been implicated in the development of glaucoma. This project aims to establish mice lacking the α1 subunit of the NO receptor soluble guanylate cyclase (sGCα1-/- mice) as a spontaneous mouse model for elevated IOP and POAG.

Methods: : IOP was measured serially using a TonoLab-Tonometer in age-matched female WT and sGCα1-/- mice (n=15 and 37 eyes, respectively). Trabecular meshwork in WT and sGCα1-/- was examined by light and transmission electron microscopy. Retinal whole mounts were stained for β III tubulin to visualize RGCs. Axons in optic nerve cross sections were stained with paraphenylenediamine and counted.

Results: : The IOP in sGCα1-/- mice increased significantly with age, from 14±2 mmHg at 19±1 wks to 18±3 mmHg at 37±2 wks (P<0.001). By contrast, the IOP in WT mice remained unchanged: 13±2 mmHg at 20±1 wks and 13±2 mmHg at 39±1 wks. Morphological analysis revealed an open iridocorneal angle in eyes from sGCα1-/- mice with high IOP. β III tubulin staining revealed a loss of RGCs and nerve fibers in retinas of sGCα1-/- mice that coincided with a lower axon count in optic nerves from sGCα1-/- mice than from WT mice (70±12 and 140±16 axons/high powered field, respectively, P<0.01).

Conclusions: : These findings support sGCα1-/- mice as a novel spontaneous model of POAG, providing an important tool for testing strategies that lower or prevent elevated IOP associated with POAG.

Keywords: intraocular pressure • nitric oxide • transgenics/knock-outs