Angiogenin is a potent modulator of neovascularization and inflammation that is upregulated in various human retinal diseases

Abstract

Purpose: Our lab is interested in identifying common stress-response pathways that may contribute to the initiation or progression of multiple retinal diseases. Diabetic retinopathy (DR), age-related macular degeneration (AMD), retinitis pigmentosa (RP), and uveitis are diseases with neurodegenerative, inflammatory, and neovascular features observed with variable frequency. Current treatment strategies, including laser photocoagulation and anti-inflammatory and angiostatic agents, can be insufficient. Identifying a pathological feature common to these diseases could lead to the development of a therapeutic agent effective in slowing or preventing their pathogeneses.

Methods: Cytokine levels in human aqueous and vitreous samples from patients with various retinal diseases were analyzed. Angiogenin was found to be dysregulated. Its expression was examined in four murine models of ocular neurodegeneration and/or neovascularization (RD1, RD10, RDS, Oxygen-induced retinopathy) using immunofluorescence. Angiogenin was overexpressed in mouse Müller glia using ShH10 virus (ShH10-Ang) and the retinas were monitored in vivo for phenotypic and functional changes using optical coherence tomography, ICG angiography, and electroretinography. Immunofluorescence was also employed on flat-mounted retinas and cryopreserved sectioned tissues.

Results: We detected significantly elevated levels of angiogenin in aqueous and vitreous samples from human patients with DR, AMD, RP, and uveitis. Similarly, in murine disease models we detected elevated levels of angiogenin in Müller glia. Angiogenin was experimentally potentiated in the Müller glia of wild type mice using ShH10-Ang. Three days post injection, pronounced neovascularization and clear signs of inflammation were observed both in vivo and in histological preparations. Electroretinography revealed neuronal dysfunction as early as eight days post injection.

Conclusions: Angiogenin is dysregulated in a number of human ocular diseases and murine models, suggesting its upregulation may be a common stress-activated response. Elucidating its beneficial and pathological functions could provide insights into retinal disease progression and provide a potential novel target for therapeutic intervention.

Keywords: 700 retinal neovascularization • 557 inflammation • 603 Muller cells