Intravitreal ECE-1 siRNA Treatment for Retinal Dysfunction during Early Diabetes
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abstract
Retinopathy is a major complication of diabetes mellitus and a leading cause of blindness in the United States. Treatment modalities for restoring retinal function are relatively ineffective. Although alterations of both neural and vascular retina have been reported, the temporal relationship between neural retina damage and vasomotor dysfunction of resistance arterioles, the major site for blood flow regulation to theinner retina, remains unclear. This is important since reduced retinal blood flow occurs during early diabetes, which suggests that dysfunction of arterioles leading to ischemia may contribute to neural retina damage. However, mechanisms contributing to retinal vasomotor dysfunction in diabetes that are amenable to treatment prior to establishment of overt pathology remain unclear. Furthermore, development of an animal model of diabetes relevant to the human retinal microcirculation and its pathophysiology is lacking. To address these clinically important issues, we have developed a streptozocin-induced type 1 diabetes model in the pig, which we have shown resembles human in retinal vasomotor regulation/dysregulation. Our preliminary data show that within 2 wk of diabetes, endothelium-dependent nitric oxide (NO)-mediated dilation of retinal arterioles is impaired and constriction to big endothelin-1, the endothelin-1 (ET-1) precursor substrate for endothelin-converting enzyme- 1 (ECE-1), is enhanced without altering constriction to ET-1 per se. Although the smooth muscle response to ET-1 is unaltered, the ability to synthesize ET-1 is increased due to elevated ECE-1 expression. A potential harmful role for increased ET-1, besides its potent vasoconstrictor action, is its ability to inhibit NO production; however, whether ET-1 synthesis blockade can improve dilation during diabetes is unknown. Since retinal lactate level is increased within 2-wk diabetes and scotopic b-wave amplitude is reduced during 6-wk but not 2- wk diabetes, it appears vasomotor dysfunction promoting ischemia precedes inner neural retina damage. We recently detected ECE-1 in retinal arterioles but not neural retina, so ECE-1 may provide a specific vascular target for improving retinal arteriolar function, along with secondary amelioration of neural retina function, during early diabetes. Thus, the goal of this study is to understand the role of the ET-1 system in initiating retinal dysfunction by optimizing delivery of small interfering RNA (siRNA) via intravitreal injection to restore retinal arteriolar function. We will test the hypothesis that eary diabetes augments ECE-1 activity and ET-1 production leading to impairment of endothelium-dependent NO-mediated dilation of retinal arterioles prior to alteration of the neural retina function. To support the hypothesis and to test the feasibility of siRNA treatment, we will pursue the following specific aim: Determine whether molecular knockdown of ECE-1 in retinal arterioles improves diabetes-induced dysfunction of endothelium and neural retina. This innovative study will provide the first longitudinal assessment of both vascular and neural function in the retina from the same animal during diabetes, which will help in our understanding of retinal pathogenesis and development of new therapies for early treatment.
