Purchase this article with an account.
J. F. Tucker, B. W. Jones, C. D. Gerstner, T. P. Kennedy, N. V. Rao, G. D. Prestwich, B. K. Ambati, R. E. Marc; Pharmacological Prevention of RAGE-Mediated RPE Damage: Implications for Age-Related Macular Degeneration. Invest. Ophthalmol. Vis. Sci. 2009;50(13):702.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Oxidative damage appears to play an important role in the pathogenesis of AMD. A2E and other oxidatively damaged molecules accumulate in the retina with advancing age and increasing oxidative stress and form a significant component of drusen. The receptor for advanced glycation endproducts (RAGE), which recognizes many of these molecules and initiates inflammatory responses, is associated AMD and localizes to the RPE and Bruch's membrane. Furthermore, RAGE activation has been shown to induce cell death in cultured ARPE-19 cells. We hypothesize that RAGE-mediated damage to the RPE contributes to the pathogenesis of AMD and that RAGE-inhibiting compounds may show promise as therapeutic agents.
Cultured ARPE-19 cells were exposed to various concentrations of RAGE ligands and novel sulfated polysaccharide RAGE antagonists (GlycoMira, Inc, ParinGenix Inc.). Cells were assayed for response to these compounds by western blot and ELISA for pro-inflammatory markers and immunocytological examination of cell stress and cell death.
ARPE-19 cells treated with RAGE ligands exhibited a significant degree of cell death as well as upregulation of RAGE and other pro-inflammatory markers. Cell death proceeded in a progressive cascading fashion. The measured effects of RAGE ligand administration were mitigated to different degrees by co-administration of various RAGE antagonists.
The cascading pattern of cell death observed implies that RAGE access on non-apical surfaces may be required for the observed response, and suggests a potential role for mechanical disruption of the RPE and Bruch’s membrane in the pathological response to oxidative injury. The successful rescue of the induced disease phenotype indicates that the novel RAGE antagonists employed may hold promise as a preventative treatment for AMD and other oxidative damage-related retinal diseases.
This PDF is available to Subscribers Only