Clinical trials suggest that Angiotensin Converting Enzyme inhibitors (ACEi) slow the progression of diabetic retinopathy. However, there is little experimental evidence that Angiotensin II (Ang II) is a critical pathogenetic factor in the development of diabetic retinopathy. ACEi's act systemically decreasing blood pressure (BP) and may also act by decreasing local Ang II effects or by non-Ang-dependent mechanisms. Vascular Endothelial Growth Factor (VEGF) is responsible for retinal neovascularization and stimulates expression of Intercellular Adhesion Molecule-1 (ICAM-1), causing leukostasis, capillary plugging and 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 II induces retinal leukostasis in vivo. We hypothesize that: a) inhibitionof Ang II ameliorates diabetic retinopathy by mechanisms independent of BP reduction and b) Ang II acts via ROS and VEGF R to increase the expression of retinal leukocyte adhesion molecules, leukostasis, capillary plugging and 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-induced diabetes (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 inhibit the renin angiotensin system (RAS). We expect that retinopathy is decreased by ramipril and perhaps Iosartan but not 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 ATl inhibitor in SZD rats (1-2 weeks), and in normal rats 48 hrs after ivt VEGF, and b) increase after ivt Ang II, and whether anti-oxidants or SU5416 inhibit these 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.
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