Pigment-epithelium-derived factor suppresses expression of receptor for advanced glycation end products in the eye of diabetic rats.
The interaction of advanced glycation end products (AGEs) and their receptor (RAGE) elicits inflammatory and proliferative responses in retinal vascular wall cells, thereby being involved in the pathogenesis of diabetic retinopathy. Recently, pigment-epithelium-derived factor (PEDF) has also been shown to play a role in diabetic retinopathy. However, the effects of PEDF on RAGE gene expression remain to be elucidated. Therefore, we investigated here whether PEDF could prevent diabetes- or AGE-induced RAGE gene expression and the way that it might achieve this effect. Administration of PEDF or pyridoxal phosphate, an AGE inhibitor, suppressed RAGE gene expression in the eye of streptozotocin-induced diabetic rats. Further, intravenous injection of AGEs to normal rats increased RAGE gene expression, which was also blocked by PEDF. In vitro, PEDF or an antioxidant N-acetylcysteine blocked the AGE-induced RAGE gene induction in microvascular endothelial cells. In addition, PEDF completely inhibited superoxide generation and NF-kappaB activation in AGE-exposed endothelial cells. These results demonstrated that PEDF could inhibit diabetes- or AGE-induced RAGE gene expression by blocking the superoxide-mediated NF-kappaB activation. Our present study suggests that pharmacological upregulation or substitution of PEDF may play a protective role against diabetic retinopathy by attenuating the deleterious effect of AGEs.
Yamagishi
Sho-Ichi
S
Department of Internal Medicine, Kurume University School of Medicine, Kurume, Japan. shoichi@med.kurume-u.ac.jp
Matsui
Takanori
T
Nakamura
Kazuo
K
Yoshida
Takafumi
T
Takeuchi
Masayoshi
M
Inoue
Hiroyoshi
H
Yoshida
Yumiko
Y
Imaizumi
Tsutomu
T
D000328:Adult; D000818:Animals; D002478:Cells, Cultured; D017931:DNA Primers / Q000737:chemistry; D003921:Diabetes Mellitus, Experimental / Q000235:genetics* / Q000378:metabolism; D003930:Diabetic Retinopathy / Q000235:genetics* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005136:Eye Proteins / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D017127:Glycation End Products, Advanced / Q000494:pharmacology; D006801:Humans; D007275:Injections, Intravenous; D016328:NF-kappa B / Q000378:metabolism; D009414:Nerve Growth Factors / Q000494:pharmacology*; D011732:Pyridoxal Phosphate / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015843:Serpins / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism; D015533:Transcriptional Activation; D000099174:Pigment Epithelium-Derived Factor
D017931:DNA Primers; D005136:Eye Proteins; D017127:Glycation End Products, Advanced; D016328:NF-kappa B; D009414:Nerve Growth Factors; D011732:Pyridoxal Phosphate; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D015843:Serpins; D013481:Superoxides; D000099174:Pigment Epithelium-Derived Factor