title: Blockade of angiotensin II attenuates VEGF-mediated blood-retinal barrier breakdown in diabetic retinopathy.
abstract: Diabetic retinopathy (DR) is the leading cause of vision loss as a major complication of diabetes mellitus. The blood-retinal barrier (BRB) breakdown is a critical early event in the pathogenesis of DR. It has been known that the rennin-angiotensin system (RAS) is important in the progression of the DR via angiotensin II (Ang II), the effector of RAS. In this study, we showed that blockade of Ang II attenuates vascular endothelial growth factor (VEGF)-mediated BRB breakdown in DR. In streptozotocin-induced diabetes, retinal vascular permeability increased with upregulation of VEGF, where Ang II and its receptors were upregulated. Ang II induced VEGF expression in retinal endothelial cells accompanied by loss of tight junction proteins. However, the blockade of Ang II by perindopril, an angiotensin converting enzyme (ACE) inhibitor, inhibited upregulation of VEGF, and prevented the loss of tight junction proteins. Moreover, inhibition of Ang II by perindopril attenuated increased vascular permeability of diabetic retina accompanied by recovery of tight junction proteins in retinal vessels. Therefore, we suggest that the RAS involves in increased vascular permeability during early stage of DR, which is mediated by VEGF. Furthermore, the ACE inhibitor may have a therapeutic potential in the treatment of diabetic BRB breakdown.
authors.affiliation: Fight against Angiogenesis-Related Blindness (FARB) Laboratory, Department of Ophthalmology, Seoul National University College of Medicine & Seoul Artificial Eye Center, Clinical Research Institute, Seoul National University Hospital, Seoul, Korea.
authors.forename: Jeong Hun
authors.initials: JH
authors.lastname: Kim
authors.forename: Jin Hyoung
authors.initials: JH
authors.lastname: Kim
authors.forename: Young Suk
authors.initials: YS
authors.lastname: Yu
authors.forename: Chang Sik
authors.initials: CS
authors.lastname: Cho
authors.forename: Kyu-Won
authors.initials: KW
authors.lastname: Kim
mesh_terms: D000804:Angiotensin II / Q000037:antagonists & inhibitors* / Q000502:physiology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001813:Blood-Retinal Barrier / Q000473:pathology*; D002199:Capillary Permeability; D002460:Cell Line; D003911:Dextrans / Q000493:pharmacokinetics; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D003930:Diabetic Retinopathy / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D042783:Endothelial Cells / Q000378:metabolism; D005452:Fluoresceins / Q000493:pharmacokinetics; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D020913:Perindopril / Q000494:pharmacology; D012160:Retina / Q000166:cytology; D019108:Tight Junctions / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000502:physiology
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D003911:Dextrans; D005452:Fluoresceins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C052526:fluorescein-dextran; C467480:vascular endothelial growth factor A, mouse; D000804:Angiotensin II; D020913:Perindopril