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N. J. O'Connor, A. Veerappan, R. B. Silver; Mast Cells in Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2010;51(13):5627.
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The renin-angiotensin system (RAS) is known to play a pathologic role in diabetic retinopathy (DR). Based on our previous findings that mast cells (MC) are a source of renin, the rate-limiting enzyme in the RAS, and that MC appear in rat retina in streptozotocin (STZ) induced hyperglycemia, we hypothesize that MC play a key role in the vascular leakiness associated with developing DR.
Sprague-Dawley rats were injected with STZ (IP, 50mg/kg) and maintained for 2-, 8-, and 16-weeks. Hyperglycemia (>300 mg glucose/dl) was verified weekly. The mast cell stabilizer cromolyn was administered either via osmotic mini-pump (24 mg/kg/day) or by topical administration (20 mg/ml, 2-drops b.i.d.). At 2-weeks post-STZ injection, vascular leakage was assessed by absorbance measurements of albumin-bound Evan’s Blue dye extracted from the retinas of blood-cleared rats. Retinal VEGF levels were measured by ELISA. Both leakage and VEGF values were normalized to retinal dry-weight. At 8- and 16-weeks post-STZ injection, retinal whole-mounts were analyzed for immunolocalization of MC to the retinal vasculature using antibodies against the MC specific receptor FCεRI and isolectin, respectively. Additionally, human waste-tissue specimens of DR fibrotic lesions were immuno-screened for MC and renin.
Quantitative measurement of retinal vascular leakage demonstrated that increased leakiness in hyperglycemic rats (2.5±0.5 mg/ml/hour/mg tissue; n=3) was significantly reduced (p0.05) from control (0.8±0.04; n=3). Similarly, increased retinal VEGF levels in hyperglycemic rats (269.2±35.0 pgm/ml/mg tissue; n=3) were significantly reduced (p0.05) from control (86.2±26.0; n=5). Wholemount retinal preparations labeled for MC verified MC in retina during the STZ model. Immuno-labeling of human diabetic retinopathic plaques revealed the presence of renin-positive MC.
MC appear critical to the development of retinal vascular leakiness in the STZ model. We propose that MCs promote DR and present a novel therapeutic target in the treatment of DR.
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