Abstract P134: Peg-arginase 1 Limits Vascular Complications Of Type 2 Diabetes

Background: Distinct from its role in the urea cycle, the function of arginase 1 (A1) in regulating inflammatory responses has been demonstrated to be an intriguing target for controlling chronic, neuroinflammatory disease. Arginase competes with nitric oxide synthase (NOS) isoforms for their common substrate, L-arginine. Inflammatory cytokines increase expression of inducible NOS (iNOS) resulting in oxidant stress. Our group has recently shown that the polyethylene glycol-linked arginase 1 (PEG-A1) formulation, which provides enzyme stability, is a promising treatment that can counteract the destructive effects of neuro-inflammation and oxidative stress in ischemic retinal disease. This study assessed the efficacy of systemic PEG-A1 treatment in protecting the retinal neurovascular system from the effects of chronic hyperglycemia in a well-established murine model of type 2 diabetes. Methods: Studies were performed using 16-week-old obese, diabetic db/db mice to examine effects of chronic hyperglycemia and dyslipidemia on the retina. Lean Db/db littermates served as controls (n= 7/group). The db/db mice (n= 8/group) were treated with PEG-A1 (25 mg/kg IP) or PEG alone (control) 7 times over 2 weeks. Activation of the inflammasome pathway was examined by Western blots. Immuno-labeling of 4-HNE was used to quantify oxidative stress. Breakdown of the blood retinal barrier (BRB) was examined via albumin extravasation. Results: Expression of inflammasome pathway proteins, iNOS, caspase 1, IL-1β, and TNFα were upregulated in conjunction with increased cell death and breakdown of the BRB in db/db mice compared to controls. PEG-A1 treatment of the db/db mice significantly decreased the expression of iNOS, IL-1β, and TNFα, while reducing oxidative stress and preserving the BRB, as evidenced by decreased albumin leakage compared to db/db mice treated with PEG. Conclusions: Chronic diabetes increases retinal inflammation, oxidative stress and BRB disruption. We hypothesize that systemic PEG-A1 administration provides significant anti-inflammatory and anti-oxidant protection while inhibiting BRB breakdown in the db/db obese, diabetic mouse by decreasing L-arginine availability for iNOS and thereby inhibiting its expression/activity.