Intraocular Sustained Release of EPO-R76E Mitigates Glaucoma Pathogenesis by Activating the NRF2/ARE Pathway

Author:

Naguib Sarah1ORCID,DeJulius Carlisle R.2,Backstrom Jon R.3,Haider Ameer A.1ORCID,Ang John M.1,Boal Andrew M.1,Calkins David J.13ORCID,Duvall Craig L.2,Rex Tonia S.13

Affiliation:

1. Neuroscience Program, Vanderbilt University, Nashville, TN 37232, USA

2. Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37232, USA

3. Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, TN 37232, USA

Abstract

Erythropoietin (EPO) is neuroprotective in multiple models of neurodegenerative diseases, including glaucoma. EPO-R76E retains the neuroprotective effects of EPO but diminishes the effects on hematocrit. Treatment with EPO-R76E in a glaucoma model increases expression of antioxidant proteins and is neuroprotective. A major pathway that controls the expression of antioxidant proteins is the NRF2/ARE pathway. This pathway is activated endogenously after elevation of intraocular pressure (IOP) and contributes to the slow onset of pathology in glaucoma. In this study, we explored if sustained release of EPO-R76E in the eye would activate the NRF2/ARE pathway and if this pathway was key to its neuroprotective activity. Treatment with PLGA.EPO-E76E prevented increases in retinal superoxide levels in vivo, and caused phosphorylation of NRF2 and upregulation of antioxidants. Further, EPO-R76E activates NRF2 via phosphorylation by the MAPK pathway rather than the PI3K/Akt pathway, used by the endogenous antioxidant response to elevated IOP.

Funder

DoD grants

NEI grants

NIH NIGMS grants

NIBIB

GRFP

Potocsnak Discovery Grant in Regenerative Medicine

Stein Innovation Award

Vanderbilt University Medical Center

NIH grants

Publisher

MDPI AG

Subject

Cell Biology,Clinical Biochemistry,Molecular Biology,Biochemistry,Physiology

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