Role of Arginase 2 in Murine Retinopathy Associated with Western Diet-Induced Obesity

Abstract

Western diet-induced obesity is linked to the development of metabolic dysfunctions, including type 2 diabetes and complications that include retinopathy, a leading cause of blindness. Aberrant activation of the inflammasome cascade leads to the progression of obesity-induced pathologies. Our lab showed the critical role of arginase 2 (A2), the mitochondrial isoform of this ureahydrolase, in obesity-induced metabolic dysfunction and inflammation. A2 deletion also has been shown to be protective against retinal inflammation in models of ischemic retinopathy and multiple sclerosis. We investigated the effect of A2 deletion on western diet-induced retinopathy. Wild-type mice fed a high-fat, high-sucrose western diet for 16 weeks exhibited elevated retinal expression of A2, markers of the inflammasome pathway, oxidative stress, and activation of microglia/macrophages. Western diet feeding induced exaggerated retinal light responses without affecting visual acuity or retinal morphology. These effects were reduced or absent in mice with global A2 deletion. Exposure of retinal endothelial cells to palmitate and high glucose, a mimic of the obese state, increased expression of A2 and inflammatory mediators and induced cell death. These effects, except for A2, were prevented by pretreatment with an arginase inhibitor. Collectively, our study demonstrated a substantial role of A2 in early manifestations of diabetic retinopathy.

Light Environment Influences Developmental Programming of the Metabolic and Visual Systems in Mice

“…6 ). HFD alone also impaired visual function, the impact of which has not been well studied 59 ; a previous study utilizing a high-fat, high-sucrose diet reported no differences, 60 whereas another reported decreased OMR responses after 2 months of HFD (Douglass, AJ et al IOVS 2020;61:ARVO E-Abstract 2245). However, an optical coherence tomography angiography (OCTA) study uncovered rapid neurovascular decoupling after sugary beverage consumption, 61 suggesting clinical relevance for acute nutritional challenge.…”

Is the Arginase Pathway a Novel Therapeutic Avenue for Diabetic Retinopathy?

“…The deletion of A2 significantly protected against this obesity-induced photoreceptor abnormality. This protective effect of the A2 deletion was accompanied by reduced retinal inflammation, oxidative stress, and microglia/macrophage activation [76]. Further study is required to elucidate the differential roles of the two arginase isoforms in the various retinal complications of type 1 and type 2 diabetes.…”

“…A2 deletion protected against the obesity-induced abnormalities in the ERG responses. [76] OIR Mice A2 retinal levels are increased during the ischemic phase of OIR. A2 deletion ameliorated OIR-induced neurovascular alterations.…”

Novel Therapeutics for Diabetic Retinopathy and Diabetic Macular Edema: A Pathophysiologic Perspective

“…Nuclear factor erythroid 2-related factor 2 (Nrf2) is a novel potential target that upregulates transcription of antioxidant proteins and has shown great promise in the treatment of retinal diseases (Nakagami, 2016). Finally, our group has demonstrated the complex roles of the arginase isoforms in the development and progression of DR, illustrating the potential therapeutic benefit of targeting these enzymes in diseases that impact the neurovasculature (Patel et al, 2013;Caldwell et al, 2015;Shosha et al, 2016Shosha et al, , 2021Atawia et al, 2020).…”