Inhibition of protein kinase C delta attenuates blood-retinal barrier breakdown in diabetic retinopathy.
Vision loss in diabetic retinopathy is due to macular edema characterized by increased vascular permeability, which involves phosphorylation associated with activation of protein kinase C (PKC) isoforms. Herein, we demonstrated PKC delta inhibition could prevent blood-retinal barrier breakdown in diabetic retinopathy. Increased vascular permeability of diabetic retina was accompanied by a decrease of zonula occludens (ZO)-1 and ZO-2 expression. In diabetic retina and advanced glycation end product-treated human retinal microvascular endothelial cells, vascular leakage and loss of ZO-1 and ZO-2 on retinal vessels were effectively restored or prevented with treatment of rottlerin, transfection of PKC-delta-DN, or siRNA for PKC delta. Interestingly, PKC delta translocated from cytosol to membrane in advanced glycation end product-treated human retinal microvascular endothelial cells, which was blocked by PKC delta inhibition. Taken together, PKC delta activation, related to its subcellular translocation, is involved in vascular permeability in response to diabetes, and inhibition of PKC delta effectively restores loss of tight junction proteins in retinal vessels. Therefore, we suggest that inhibition of PKC delta could be an alternative treatment to blood-retinal barrier breakdown in diabetic retinopathy.
Kim
Jeong-Hun
JH
Department of Ophthalmology, College of Medicine, Seoul National University & Seoul Artificial Eye Center Clinical Research Institute, Seoul National University Hospital, Seoul 151-744, Republic of Korea.
Kim
Jin Hyoung
JH
Jun
Hyoung-Oh
HO
Yu
Young Suk
YS
Kim
Kyu-Won
KW
D000818:Animals; D001813:Blood-Retinal Barrier / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology* / Q000503:physiopathology; D002199:Capillary Permeability / Q000187:drug effects; D003600:Cytosol / Q000187:drug effects / Q000201:enzymology; D003930:Diabetic Retinopathy / Q000201:enzymology* / Q000473:pathology* / Q000503:physiopathology; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D005799:Genes, Dominant / Q000235:genetics; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D055806:Microvessels / Q000473:pathology; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D034741:RNA, Small Interfering / Q000378:metabolism; D012171:Retinal Vessels / Q000473:pathology; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
D008565:Membrane Proteins; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A; D051745:Protein Kinase C-delta