Protective role of pigment epithelium-derived factor (PEDF) in early phase of experimental diabetic retinopathy.
BACKGROUND
Pigment epithelium-derived factor (PEDF) is the most potent inhibitor of angiogenesis in the mammalian eye, thus suggesting that PEDF may protect against proliferative diabetic retinopathy. However, a role for PEDF in early diabetic retinopathy remains to be elucidated. We investigated here whether and how PEDF could prevent the development of diabetic retinopathy.


METHODS
Streptozotocin-induced diabetic rats were treated with or without intravenous injection of PEDF for 4 weeks. Early neuronal derangements were evaluated by electroretinogram (ERG) and immunofluorescent staining of glial fibrillary acidic protein (GFAP). Expression of PEDF and 8-hydroxydeoxyguanosine (8-OHdG), a marker of oxidative stress, was localized by immunofluorescence. Vascular endothelial growth factor (VEGF) and p22phox expression were evaluated with western blots. Breakdown of blood retinal barrier (BRB) was quantified with fluorescein isothiocynate (FITC)-conjugated dextran. NADPH oxidase activity was measured with lucigenin luminescence.


RESULTS
Retinal PEDF levels were reduced, and amplitudes of a- and b-wave in the ERG were decreased in diabetic rats, which were in parallel with GFAP overexpression in the Müller cells. Further, retinal 8-OHdG, p22phox and VEGF levels and NADPH oxidase activity were increased, and BRB was broken in diabetic rats. Administration of PEDF ameliorated all of the characteristic changes in early diabetic retinopathy.


CONCLUSIONS
Results suggest that PEDF could prevent neuronal derangements and vascular hyperpermeability in early diabetic retinopathy via inhibition of NADPH oxidase-driven oxidative stress generation. Substitution of PEDF may offer a promising strategy for halting the development of diabetic retinopathy.
Yoshida
Yumiko
Y
Department of Ophthalmology, Kurume University School of Medicine, Kurume, Japan.
Yamagishi
Sho-Ichi
S
Matsui
Takanori
T
Jinnouchi
Yuko
Y
Fukami
Kei
K
Imaizumi
Tsutomu
T
Yamakawa
Ryoji
R
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001813:Blood-Retinal Barrier / Q000502:physiology; D001835:Body Weight; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000503:physiopathology*; D003930:Diabetic Retinopathy / Q000503:physiopathology* / Q000517:prevention & control; D004596:Electroretinography; D005136:Eye Proteins / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007091:Image Processing, Computer-Assisted; D008297:Male; D019255:NADPH Oxidases / Q000378:metabolism; D009414:Nerve Growth Factors / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D009928:Organ Specificity; D018384:Oxidative Stress; D051381:Rats; D017208:Rats, Wistar; D012160:Retina / Q000378:metabolism; D015843:Serpins / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D042442:Vascular Endothelial Growth Factors / Q000378:metabolism; D000099174:Pigment Epithelium-Derived Factor
D000080242:8-Hydroxy-2'-Deoxyguanosine; D001786:Blood Glucose; D003849:Deoxyguanosine; D005136:Eye Proteins; D005904:Glial Fibrillary Acidic Protein; D019255:NADPH Oxidases; D009414:Nerve Growth Factors; D015843:Serpins; D042442:Vascular Endothelial Growth Factors; D000099174:Pigment Epithelium-Derived Factor; C515768:Cyba protein, rat