TY - JOUR
T1 - Suppression of retinal peroxisome proliferator-activated receptor γ in experimental diabetes and oxygen-induced retinopathy
T2 - Role of NADPH oxidase
AU - Tawfik, Amany
AU - Sanders, Tammy
AU - Kahook, Khalid
AU - Akeel, Sara
AU - Elmarakby, Ahmed
AU - Al-Shabrawey, Mohamed
PY - 2009/2
Y1 - 2009/2
N2 - PURPOSE. Recently, the authors have shown that NADPH oxidase is positively correlated with increased leukocyte adhesion and vascular leakage in diabetes and neovascularization in oxygen-induced retinopathy (OIR). Peroxisome proliferatoractivated receptor gamma (PPARγ) agonists have been shown to prevent vascular inflammation and leakage in an experimental model of diabetes. The goal of this study was to investigate whether there is a link between NADPH oxidase and PPARγ that leads to vascular dysfunction in diabetic retina or OIR. METHODS. Diabetes was induced with streptozotocin in wildtype mice or NOX2 knockout mice. One group of wild-type mice was treated with apocynin. Bovine retinal endothelial cells (BRECs) were treated with normal glucose (5 mM) or high glucose (25 mM) in the presence or absence of superoxide dismutase (SOD) or NADPH oxidase inhibitors (apocynin or diphenyleneiodonium [DPI]). Western blotting and immunofluorescence were used to evaluate PPARγ expression. Activation of nuclear factor (NF)κB was measured using the transcription factor assay kit and Western blot analysis of phospho-NFκB. PPARγ expression was also tested in OIR and lipopolysaccharide-induced retinal inflammation. RESULTS. Retinal expression of PPARγ was suppressed in experimental models of diabetes, OIR, and retinal inflammation. This was associated with the activation of NFκB in the diabetic retina. These effects were prevented by apocynin or deletion of NOX2. PPARγ expression was also suppressed in endothelial cells treated with high glucose, and this was prevented by apocynin, DPI, and SOD. CONCLUSIONS. Suppression of PPARγ is involved in the pathogenesis of diabetic retinopathy and OIR. NADPH oxidase could be an upstream mediator of these changes.
AB - PURPOSE. Recently, the authors have shown that NADPH oxidase is positively correlated with increased leukocyte adhesion and vascular leakage in diabetes and neovascularization in oxygen-induced retinopathy (OIR). Peroxisome proliferatoractivated receptor gamma (PPARγ) agonists have been shown to prevent vascular inflammation and leakage in an experimental model of diabetes. The goal of this study was to investigate whether there is a link between NADPH oxidase and PPARγ that leads to vascular dysfunction in diabetic retina or OIR. METHODS. Diabetes was induced with streptozotocin in wildtype mice or NOX2 knockout mice. One group of wild-type mice was treated with apocynin. Bovine retinal endothelial cells (BRECs) were treated with normal glucose (5 mM) or high glucose (25 mM) in the presence or absence of superoxide dismutase (SOD) or NADPH oxidase inhibitors (apocynin or diphenyleneiodonium [DPI]). Western blotting and immunofluorescence were used to evaluate PPARγ expression. Activation of nuclear factor (NF)κB was measured using the transcription factor assay kit and Western blot analysis of phospho-NFκB. PPARγ expression was also tested in OIR and lipopolysaccharide-induced retinal inflammation. RESULTS. Retinal expression of PPARγ was suppressed in experimental models of diabetes, OIR, and retinal inflammation. This was associated with the activation of NFκB in the diabetic retina. These effects were prevented by apocynin or deletion of NOX2. PPARγ expression was also suppressed in endothelial cells treated with high glucose, and this was prevented by apocynin, DPI, and SOD. CONCLUSIONS. Suppression of PPARγ is involved in the pathogenesis of diabetic retinopathy and OIR. NADPH oxidase could be an upstream mediator of these changes.
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U2 - 10.1167/iovs.08-2005
DO - 10.1167/iovs.08-2005
M3 - Article
C2 - 18806296
AN - SCOPUS:59449102868
SN - 0146-0404
VL - 50
SP - 878
EP - 884
JO - Investigative Ophthalmology and Visual Science
JF - Investigative Ophthalmology and Visual Science
IS - 2
ER -