title: The renin-angiotensin system influences ocular endothelial cell proliferation in diabetes: transgenic and interventional studies.
abstract: Neovascularization in the retina and iris of diabetic patients is a major cause of severe visual loss. However, study of these lesions is compromised by the lack of a comparable diabetic rodent model. Because the vasoactive and angiogenic agent, angiotensin II, is involved in diabetic microvascular disease, we aimed to determine whether endothelial cell proliferation could be induced in the retinae and irides of hypertensive transgenic (mRen-2)27 rats that display an enhanced extra-renal renin-angiotensin system (RAS), including the eye. Six-week-old Ren-2, spontaneously hypertensive, and Sprague-Dawley rats received either streptozotocin or control vehicle and were studied for 36 weeks. Additional nondiabetic and diabetic Ren-2 rats were treated throughout with the angiotensin-converting enzyme inhibitor lisinopril (LIS) (10 mg/kg/day in drinking water). Endothelial cell proliferation was only observed in retinae and irides of diabetic Ren-2 rats and was reduced with LIS. In diabetic Ren-2, vascular endothelial growth factor (VEGF) and VEGFR-2 mRNA were increased in retinae and irides and reduced with LIS. Diabetes activated ocular renin in Ren-2 but not Sprague-Dawley rats. The diabetic Ren-2 rat is a model of intraocular endothelial cell proliferation that can be attenuated by RAS blockade via VEGF-dependent pathways. RAS blockade is a potential treatment for vision-threatening diabetic microvascular complications.
authors.affiliation: Department of Physiology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Christina J
authors.initials: CJ
authors.lastname: Moravski
authors.forename: Sandford L
authors.initials: SL
authors.lastname: Skinner
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Stubbs
authors.forename: Stella
authors.initials: S
authors.lastname: Sarlos
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Kelly
authors.forename: Mark E
authors.initials: ME
authors.lastname: Cooper
authors.forename: Richard E
authors.initials: RE
authors.lastname: Gilbert
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Wilkinson-Berka
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D030801:Animals, Genetically Modified; D002908:Chronic Disease; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000150:complications / Q000473:pathology*; D003930:Diabetic Retinopathy / Q000209:etiology / Q000473:pathology*; D004195:Disease Models, Animal; D016228:Endothelial Growth Factors / Q000235:genetics / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D005123:Eye / Q000378:metabolism / Q000473:pathology; D005260:Female; D006579:Heterozygote; D017403:In Situ Hybridization; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D007498:Iris / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D017706:Lisinopril / Q000494:pharmacology; D008222:Lymphokines / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000235:genetics / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology; D012160:Retina / Q000187:drug effects / Q000473:pathology; D013311:Streptozocin; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism; D042442:Vascular Endothelial Growth Factors
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D013311:Streptozocin; D017706:Lisinopril; D040301:Vascular Endothelial Growth Factor Receptor-2; D012083:Renin