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A. G. Miller, G. Tan, R. H. Nagaraj, M. E. Cooper, J. L. Wilkinson-Berka; Candesartan Attenuates Vascular Injury in Diabetic Retinopathy by Restoring Glyoxalase I Function. Invest. Ophthalmol. Vis. Sci. 2009;50(13):4806.
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© ARVO (1962-2015); The Authors (2016-present)
Angiotensin II (ANG II) blockade is being evaluated as a treatment for diabetic retinopathy (DR). We aimed to determine if the angiotensin type 1 receptor blocker, candesartan, improves pre-clinical DR. We investigated whether interactions between ANG II and the advanced glycation end-product pathway contributes to vascular injury in DR by reduction of glyoxalase I (GLOI).
Bovine retinal endothelial cells (BREC) and retinal pericytes (BRP), were incubated with 100 nM ANG II for 24 hours. GLOI activity was assayed by measuring formation of S-D-lactoylglutathione. Apoptosis was evaluated by TUNEL staining. Ren-2 rats, with an enhanced renin-angiotensin system (RAS) were randomised into 3 groups: non-diabetic, streptozotocin diabetic, diabetic+candesartan (5mg/kg/day, gavage), and studied for 1, 4 and 20 weeks. Systolic blood pressure was recorded. Acellular capillaries were measured on retinal trypsin digests. Leukostasis was quantitated after rhodamine-concanavalinA perfusion. GLOI, intercellular adhesion molecule (ICAM-1), vascular endothelial growth factor (VEGF) and RAS component mRNA were quantitated by real-time PCR.
ANG II negatively influenced retinal cell survival with 3- and 4- fold increases in apoptotic BREC and BRP with ANG II treatment (P<0.05). In vivo, acellular capillaries increased in diabetic Ren-2 rats compared to control (4.66±0.56 vs 1.37±0.16/field, P<0.05) and were restored to control levels with candesartan (1.22±0.19, P<0.05). Leukostasis was increased in diabetes (249.8±59.1 vs control, 30.1±7.8/retina, P<0.01) and reduced with candesartan (29.0±5.6, P<0.05 vs diabetic). Retinal VEGF, ICAM-1 and RAS components were attenuated with candesartan. ANG II reduced GLOI mRNA (0.75±0.12 and 0.75±0.05 fold, P<0.05) and activity (83.3±5% and 83.6±3.7%, P<0.05) in BRP and BREC compared to control. In diabetic Ren-2 rats, GLOI mRNA was reduced (0.6±0.03 fold) compared to control, and restored with candesartan (1.02±0.15).
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