The interplay of oxidative stress and ARMS2-HTRA1 genetic risk in neovascular AMD

Abstract

Age-related macular degeneration (AMD) is the leading cause of vision loss in adults over 60 years old globally. There are two forms of advanced AMD: “dry” and “wet”. Dry AMD is characterized by geographic atrophy of the retinal pigment epithelium and overlying photoreceptors in the macular region; whereas wet AMD is characterized by vascular penetrance from the choroid into the retina, known as choroidal neovascularization (CNV). Both phenotypes eventually lead to loss of central vision. The pathogenesis of AMD involves the interplay of genetic polymorphisms and environmental risk factors, many of which elevate retinal oxidative stress. Excess reactive oxygen species react with cellular macromolecules, forming oxidation-modified byproducts that elicit chronic inflammation and promote CNV. Additionally, genome-wide association studies have identified several genetic variants in the age-related maculopathy susceptibility 2/high-temperature requirement A serine peptidase 1 (ARMS2-HTRA1) locus associated with the progression of late-stage AMD, especially the wet subtype. In this review, we will focus on the interplay of oxidative stress and HTRA1 in drusen deposition, chronic inflammation, and chronic angiogenesis. We aim to present a multifactorial model of wet AMD progression, supporting HTRA1 as a novel therapeutic target upstream of vascular endothelial growth factor (VEGF), the conventional target in AMD therapeutics. By inhibiting HTRA1’s proteolytic activity, we can reduce pro-angiogenic signaling and prevent proteolytic breakdown of the blood-retina barrier. The anti-HTRA1 approach offers a promising alternative treatment option to wet AMD, complementary to anti-VEGF therapy.

Molecular Genetic Mechanisms in Age-Related Macular Degeneration

“…These variants are in high linkage disequilibrium (LD), and most studies to date have been unable to statistically distinguish between them. It is therefore unclear to date which of ARMS2 or HTRA1 is responsible for increased AMD risk [ 306 ]. Moreover, the exact structure and function of ARMS2 and HTRA1 remain unclear.…”

“…Local ARMS2 dysfunction may play a role in oxidative stress and damage to the retina [ 306 , 307 ]. Early studies suggested that ARMS2 localizes to the outer mitochondrial membrane in photoreceptors and RPE cells [ 302 , 307 , 308 ], although this finding has been disputed [ 309 , 310 ].…”

“…Finally, ARMS2 has recently been implicated in the local inflammatory response secreted by macrophages to activate the complement cascade and clear cellular debris [ 311 ]. HTRA1, on the other hand, has been implicated in a broad range of physiologic processes, including ECM remodeling and TGF-β cytokine signaling [ 306 ]. Its most prominent roles appear to be in ECM deposition, angiogenesis, and regulation of local subretinal inflammation [ 294 , 312 , 313 ].…”

“…High-risk variants that reduce HTRA1 expression at the RPE–BrM interface may therefore give rise to AMD phenotypes due to loss of its protective function against the effects of advancing age [ 314 ]. Some have recently argued that the weight of the evidence to date supports HTRA1 , rather than ARMS2 , as the main causal genetic factor of the two associated with AMD [ 306 ].…”

Sodium-Iodate Injection Can Replicate Retinal Degenerative Disease Stages in Pigmented Mice and Rats: Non-Invasive Follow-Up Using OCT and ERG

“…Endogenous local oxidative stress factors on the RPE and retina include the daily renewal and digestion of (oxidized) photoreceptor outer segments, their intrinsically high metabolic rate, high dissolved oxygen concentration, and dependency on mitochondrial oxidative phosphorylation for proper function [ 35 , 36 ]. As a result, with aging, the RPE contains relatively high concentrations of oxidation-modified lipids and proteins, which probably contribute to the development of AMD over time [ 35 , 37 , 38 ]. Moreover, as people age, BrM’s permeability also decreases and a lipid wall builds up, hindering the reciprocal transport of nutrients and (oxidized) waste products between the RPE to the choroid [ 39 , 40 ].…”