Lack of the P2X7receptor protects against AMD-like defects and microparticle accumulation in a chronic oxidative stress-induced mouse model of AMD.
The P2X7receptor (P2X7R) is an ATP-gated ion channel that is a key player in oxidative stress under pathological conditions. The P2X7R is expressed in the retinal pigmented epithelium (RPE) and neural retina. Chronic oxidative stress contributes to the pathogenesis of age-related macular degeneration (AMD). Mice lacking Cu, Zn superoxide dismutase (Sod1) developed chronic oxidative stress as well as AMD-like features, but whether the P2X7R plays a causative role in oxidative stress-induced AMD is unknown. Thus, the main purpose of this study was to test if concurrent knockout (KO) of P2X7R could block AMD-like defects seen in Sod1 KO mice. Using multiple approaches, we demonstrate that Sod1 KO causes AMD-like defects, including positive staining for oxidative stress markers, 3-nitrotyrosine and carboxymethyl lysine, thinning of the RPE and retina, thickening of Bruch's membrane, presence of basal laminar and linear deposits, RPE barrier disruption and accumulation of microglia/macrophages. Moreover, we find that Sod1 KO mice accumulate more microparticles (MPs) within RPE/choroid tissues. Concurrent KO of the P2X7R protects against AMD-like defects and MP accumulation in Sod1 KO mice. Together, we show for the first time, that deficiency of P2X7R prevents in vivo oxidative stress-induced accumulation of MPs and AMD-like defects. This work could potentially lead to novel therapies for AMD and other oxidative stress-driven diseases.
Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI 48105, USA.
Kyle A
KA
Carver
Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI 48105, USA.
C M
CM
Lin
Department of Ophthalmology, Duke Eye Center, Duke University, Durham, NC 27710, USA; Department of Cell Biology, Duke University, Durham, NC 27710, USA.
Catherine
C
Bowes Rickman
Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI 48105, USA. Electronic address: dlyang@umich.edu.
Dongli
D
Yang
D000818:Animals; D055252:Cell-Derived Microparticles / Q000378:metabolism*; D005260:Female; D008268:Macular Degeneration / Q000473:pathology* / Q000503:physiopathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism*; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism*; D013312:Stress, Physiological; D000072105:Superoxide Dismutase-1 / Q000235:genetics / Q000378:metabolism*
D058486:Receptors, Purinergic P2X7; C000606291:Sod1 protein, mouse; D000072105:Superoxide Dismutase-1; D010100:Oxygen
AMD; Microparticle (MP); Oxidative stress; P2X(7) receptor; Retinal pigmented epithelium (RPE); Sod1