Abstract
Purpose::
We have recently demonstrated that reactive oxygen species derived from NAD(P)H oxidase are important for retinal neovascularization in a model of oxygen-induced retinopathy (OIR) as well as microvascular dysfunction during diabetic retinopathy as indicated by leukostasis and breakdown of the blood-retinal barrier. Peroxisome Proliferator-Activated Receptor γ (PPAR γ)is a member of a ligand-activated nuclear receptor superfamily and plays a critical role in angiogenesis and inflammation. The goal of this study was to investigate the role of PPAR γ in ischemic retinopathy and whether NAD(P)H oxidase regulates its expression in retina.
Methods::
Diabetes was induced in gp91phox +/+ and -/- mice with intraperitoneal injection of streptozotocin. One group of gp91+/+ mice was treated with apocynin (10mg/kg in drinking water). Expression of 12-Lipoxygnase (inflammatory mediator) and ICAM-1 (inflammatory marker) was investigated in retina of different groups with Western blotting and immunofluroscence. PPAR γ expression in retinal vessels was investigated in retinal sections from normal and 5 weeks diabetic mice using specific anti-PPAR γ antibody and isolectin B4 to label retinal vessels. PPAR γ expression was also investigated in retinal section from mice having OIR with or without apocynin treatment.
Results::
PPARγ is expressed in retinal vessels of normal animals. However, diabetes decreases PPARγ expression, and increases the expression of 12-lipoxygenase and ICAM-1. Inhibition of NAD(P)H oxidase by apocynin or deletion of gp91phox prevents diabetes-induced changes in the expression of PPARγ, 12-lipoxygenase and ICAM-1 in retina. Interestingly, PPARγ expression is also decreased in retina of mice with OIR and is restored by apocynin treatment.
Conclusions::
Ischemic retinopathy is associated with a decrease in PPAR γ and increases in inflammatory mediator and marker 12-lipoxygenase and ICAM-1. NAD(P)H oxidase might be a key mediator of these changes.
Keywords: diabetic retinopathy • oxidation/oxidative or free radical damage • inflammation