Abstract
Purpose :
Retinal ganglion cell (RGC) injury and loss in the context of increased intraocular (IOP) are hallmark features of glaucomatous neuropathy. Understanding how different RGC subtypes respond to chronic injury may provide insight into key players involved in neuroprotection and highlight novel therapeutic targets for the treatment of glaucoma.
Methods :
Chronic IOP elevation was achieved using the silicone oil (SO)-induced ocular hypertension under-detected (SOHU) model. SO was injected into the anterior chamber of mice 8–10 weeks of age and a saline control into the contralateral eye. IOP was measured using the TonoLab tonometer weekly for up to 6 weeks. AAV-mediated OPN knockdown (KD) or overexpression (OE) in RGCs occurred at 8 weeks of age. Mice were sacrificed at 1 week and 4 weeks post-SOHU surgery for RGC subtype-specific immunohistochemistry (IHC) analysis. OPN expression was also assessed by IHC in post-mortem human retina, as well as an enzyme-linked immunosorbent assay (ELISA) to quantify OPN in the aqueous humor (AH) from patients with glaucoma.
Results :
αRGCs and intrinsic photosensitive-RGCs (ipRGCs and M1-RGCs) were found to be uniquely resilient in the setting of chronically-elevated IOP. This increased resiliency was associated with high expression of OPN, a widely-expressed constituent of the central nervous system extracellular matrix, and shown to promote optic nerve regrowth in combination with growth factors in our previous work. KD of OPN in αRGCs in the SOHU model led to a marked decrease in αRGC survival, while OE of OPN in otherwise susceptible RGCs (Foxp2-RGCs) resulted in a dramatic boost in survival after 4 weeks of elevated IOP. In post-mortem human retina, we found that OPN is expressed in large, α-like RGCs and OPN quantification by ELISA from AH of patients with glaucoma demonstrated that the degree of OPN expression is correlated with disease severity.
Conclusions :
OPN is thought to play a role tissue repair in response to neuronal injury. Work by others has implicated a neuroprotective role of OPN in ischemic stroke, spinal cord injury, and Alzheimer’s disease, and our findings suggest a novel role for OPN in promoting RGC resiliency in mouse models of glaucomatous neuropathy. Our preliminary work with post-mortem human retina, as well as analysis of AH of patients with glaucoma indicate that OPN may be a target for slowing glaucomatous neuropathy in humans.
This is a 2021 ARVO Annual Meeting abstract.