Nrf2 Activator RS9 Suppresses Pathological Ocular Angiogenesis and Hyperpermeability

Area of Science:

• Ophthalmology
• Molecular Biology
• Pharmacology

Background:

• Ocular angiogenesis, implicated in conditions like diabetic retinopathy and macular degeneration, is linked to oxidative stress.
• Nuclear factor-erythroid 2-related factor-2 (Nrf2) plays a crucial role in cellular defense against oxidative stress and inflammation.

Purpose of the Study:

• To investigate the therapeutic potential of Nrf2 activation for ocular diseases involving abnormal blood vessel growth.
• To elucidate the mechanisms by which Nrf2 activators impact ocular angiogenesis and vascular permeability.

Main Methods:

• Evaluated bardoxolone methyl (BARD) and RS9 as Nrf2 activators in human retinal microvascular endothelial cells (HRMECs).
• Assessed Nrf2 target gene expression (Ho-1, Nqo-1) in mouse retinas.
• Utilized oxygen-induced retinopathy (OIR) and laser-induced choroidal neovascularization (CNV) models in mice and monkeys, respectively.

Main Results:

• Both BARD and RS9 inhibited VEGF-induced cell migration and increased Ho-1 expression; RS9 also increased Nqo-1 expression.
• RS9 suppressed retinal neovascularization in OIR mice by reducing VEGF and increasing Nrf2, HO-1, PDGFR-β, and tight junction proteins.
• RS9 demonstrated a trend towards reducing CNV lesions and improving vascular leakage in a primate model.

Conclusions:

• Nrf2 activators represent a potential therapeutic strategy for ocular diseases characterized by pathological angiogenesis and hyperpermeability.
• RS9 exhibits promising efficacy in preclinical models, warranting further investigation for treating vision-threatening ocular conditions.