Simvastatin Attenuates Leukocyte Accumulation and Vascular Permeability in the Retina of Streptozotocin–Induced Diabetic Rats

Abstract

Abstract: : Purpose: Leukocytes play crucial roles in the pathogenesis of diabetic retinopathy. Recently, 3–hydroxy–3–methylglutaryl–coenzyme A (HMG–CoA) reductase inhibitors have been reported to exert various effects in addition to their lipid–lowering ability. We investigated the effects of simvastatin, an HMG–CoA reductase inhibitor, on leukocyte–induced changes in diabetic retinas. Methods: Diabetes was induced in Long–Evans rats with streptozotocin, and simvastatin administration was begun immediately after the induction of diabetes. Simvastatin (25mg/kg/day) was administered orally for 2 weeks after diabetes induction. The numbers of leukocytes adhered to retinal vessel endothelium and leukocytes accumulated in the retinal tissue were counted. The expression of intracellular adhesion molecule–1 (ICAM–1) was evaluated with reverse transcription polymerase chain reaction. The amount of vascular endothelial growth factor (VEGF) in the retina was evaluated with enzyme–linked immunosorbent assay. To evaluate the effects of simvastatin on leukocyte–induced endothelial cell damage, vascular permeability in the retina was measured with fluorescein–labeled dextran. Results: Two weeks treatment with simvastatin suppressed significantly the number of leukocytes adhering to retinal vessel endothelium and the number of leukocytes accumulated in the retinal tissue by 72.9% (P < 0.0001) and 41.0% (P = 0.0005) respectively. The expression of ICAM–1 was also suppressed with simvastatin. The amount of VEGF was attenuated in the simvastatin–treated group. Treatment with simvastatin markedly reduced retinal permeability (P = 0.014). Conclusions: These data suggest that simvastatin attenuats leukocyte–endothelial cell interactions and subsequent blood–retinal barrier breakdown via suppression of VEGF–induced ICAM–1 expression in the diabetic retina. Simvastatin may thus be useful in the prevention of diabetic retinopathy.

Keywords: diabetic retinopathy • diabetes • drug toxicity/drug effects