title: Adeno-Associated Virus Overexpression of Angiotensin-Converting Enzyme-2 Reverses Diabetic Retinopathy in Type 1 Diabetes in Mice.
abstract: Angiotensin-converting enzyme (ACE)-2 is the primary enzyme of the vasoprotective axis of the renin angiotensin system that regulates the classic renin angiotensin system axis. We aimed to determine whether local retinal overexpression of adenoassociated virus (AAV)-ACE2 prevents or reverses diabetic retinopathy. Green fluorescent protein (GFP)-chimeric mice were generated to distinguish resident (retinal) from infiltrating bone marrow-derived inflammatory cells and were made diabetic using streptozotocin injections. Retinal digestion using trypsin was performed and acellular capillaries enumerated. Capillary occlusion by GFP(+) cells was used to measure leukostasis. Overexpression of ACE2 prevented (prevention cohort: untreated diabetic, 11.3 ± 1.4; ACE2 diabetic, 6.4 ± 0.9 per mm(2)) and partially reversed (reversal cohort: untreated diabetic, 15.7 ± 1.9; ACE2 diabetic, 6.5 ± 1.2 per mm(2)) the diabetes-associated increase of acellular capillaries and the increase of infiltrating inflammatory cells into the retina (F4/80(+)) (prevention cohort: untreated diabetic, 24.2 ± 6.7; ACE2 diabetic, 2.5 ± 1.6 per mm(2); reversal cohort: untreated diabetic, 56.8 ± 5.2; ACE2 diabetic, 5.6 ± 2.3 per mm(2)). In both study cohorts, intracapillary bone marrow-derived cells, indicative of leukostasis, were only observed in diabetic animals receiving control AAV injections. These results indicate that diabetic retinopathy, and possibly other diabetic microvascular complications, can be prevented and reversed by locally restoring the balance between the classic and vasoprotective renin angiotensin system.
authors.affiliation: Department of Pharmacology and Therapeutics, University of Florida College of Medicine, University of Florida, Gainesville, Florida; Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: James M
authors.initials: JM
authors.lastname: Dominguez
authors.affiliation: Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Ping
authors.initials: P
authors.lastname: Hu
authors.affiliation: Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Sergio
authors.initials: S
authors.lastname: Caballero
authors.affiliation: Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Leni
authors.initials: L
authors.lastname: Moldovan
authors.affiliation: Department of Ophthalmology and Powell Gene Therapy Center, University of Florida College of Medicine, University of Florida, Gainesville, Florida.
authors.forename: Amrisha
authors.initials: A
authors.lastname: Verma
authors.affiliation: Department of Medicine, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada.
authors.forename: Gavin Y
authors.initials: GY
authors.lastname: Oudit
authors.affiliation: Department of Ophthalmology and Powell Gene Therapy Center, University of Florida College of Medicine, University of Florida, Gainesville, Florida.
authors.forename: Qiuhong
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, Indiana. Electronic address: mabgrant@iupui.edu.
authors.forename: Maria B
authors.initials: MB
authors.lastname: Grant
mesh_terms: D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D000229:Dependovirus; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000473:pathology; D003922:Diabetes Mellitus, Type 1; D003930:Diabetic Retinopathy / Q000201:enzymology* / Q000473:pathology; D015316:Genetic Therapy / Q000379:methods; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*
chemical_list: D007703:Peptidyl-Dipeptidase A; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2