Expression and Regulation of Retinal Angiotensin II

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DESCRIPTION (provided by applicant): The long-term goal of my research is to understand the role of hypertension in the pathogenesis of diabetic retinopathy. In humans and other species with vascularized retinas, the rates of glucose and oxygen utilization by the retina are 3-fold higher than in any other tissue. The retinal circulation is highly sensitive to local tissue metabolic needs and susceptible to damage from circulatory dysfunction. In diabetic patients, capillary non-perfusion has been shown to precede neovascularization. Capillary ischemia could be due at least in part to obstruction caused by abnormal or accelerated growth of vascular smooth muscle cells. The increases in angiotensin (Ang) II and insulin levels that occur in hypertension and non-insulin dependent diabetes (type 2) may contribute to this process within the small ophthalmic arteries. Thus, insulin and Ang II could act in a synergistic manner. Inhibiting the renin-angiotensin system (RAS) confers a therapeutic benefit in the treatment of diabetic retinopathy. Although the pathogenesis of diabetic retinal complications is not fully understood, emerging evidence implicates the RAS, with its mitogenic and trophic actions and its influence on angiogenesis. Ang II may be produced locally in the retina, and could play a role in the development and/or maintenance of proliferative diabetic retinopathy. Our hypothesis is that the retina is a target tissue for Ang II in rats with hypertension and/or diabetes. We will test this hypothesis in the stroke-prone spontaneously hypertensive rat (SHRSP) with streptozocin-induced diabetes, now shown to develop signs of diabetic retinopathy that are reversed by an Ang receptor antagonist. Specific aims are: 1) To determine the tissue-specific expression of Ang receptor subtype transcripts and proteins, 2) To examine tissue-specific expression of angiotensinogen, renin, angiotensin converting enzyme and Ang II in the retina. Molecular, biochemical and immunohistochemical approaches will be combined. 3) To assess the mechanism of regulation of Ang II in the retina under physiological and genetic perturbations of the RAS. Electroretinography will be used to evaluate retinal function, which will be correlated with blood pressure measured by tail cuff. These studies will not only expand our understanding of the function of the RAS in a novel tissue, but may also have important therapeutic implications. Ultimately retinal Ang receptors could be specifically targeted with selective therapeutic agents to prevent the development of proliferative diabetic retinopathy.