EXCEED THE SPACE PROVIDED. Clinical trials suggest that Angiotensin Converting Enzyme inhibitors (ACEi) slow the progressionof diabetic retinopathy. However, there is littleexperimental evidence that Angiotensin II (Ang II) is a critical pathogenetic factor inthe development of diabetic retinopathy. ACEi's act systemicallydecreasing blood pressure (BP) and may also act by decreasing localAng II effects or by non-Ang-dependent mechanisms. Vascular Endothelial Growth Factor (VEGF) is responsible for retinal neovascularization and stimulates expression of IntercellularAdhesion Molecule-1 (ICAM-1), causing leukostasis, capillary pluggingand vasopermeability. Reactive oxygen species (ROS) may mediate in part Ang II effects. We have found that Ang II is angiogenic, and that this effect is supressed by SU5416, a highly selective inhibitorof VEGF receptor (VEGF R) responses, suggesting that Ang II can act via VEGF R. In addition intravitreal Ang I! induces retinal leukostasis in vivo. We hypothesize that: a) inhibitionof Ang II ameliorates diabetic retinopathy by mechanisms independent of BP reductionand b) Ang II acts via ROS and VEGF R to increase the expression of retinal leukocyte adhesion molecules, leukostasis, capillary pluggingand vasopermeability.
Our specific aims are:
Aim 1 : To compare the effects of chronic treatment with a Ca- Channel blocker, (nifedipine), an ACEi (ramipril), and a AT1 receptor antagonist (Iosartan), on diabetic retinopathy in streptozotocin-induceddiabetes (SZD), a rat model of type 1 diabetes (12 months treatment), and in a novel model of retinal neovascularization, the Koletsky rat, a hypertensive model of type 2 diabetes, (10 months treatment). All treatments may lower BP but nifedipine does not inhibitthe renin angiotensin system (RAS). We expect that retinopathy is decreased by ramipril and perhaps Iosartan butnot nifedipine.
Aim 2 : To determine whether retinal leukostasis, capillary plugging, vasopermeability and adhesion molecules: a) decrease after treatment with either an ACEi or an Ang II ATlinhibitor in SZD rats (1-2 weeks), and in normal rats 48 hrsafter ivt VEGF, and b) increase after ivtAng II, and whether anti-oxidantsor SU5416 inhibitthese responses.
In Aim 3 we will study in retinal endothelial cells in vitro if Ang II increases adhesion molecules and leukocyte adhesion via ROS and VEGF R and the role of NF-kB. These studies will help understand the role of the RAS in diabetic retinopathy. PERFORMANCE SITE ========================================Section End===========================================
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