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An Endothelin Type A Receptor Antagonist Reverses Upregulated VEGF and ICAM-1 Levels in StreptozotocinInduced Diabetic Rat Retina Koichi Masuzawa, Katsutoshi Goto, Subrina Jesmin, Seiji Maeda, Takashi Miyauchi, Yuichi Kaji, Tetsuro Oshika, Sadao Hori Current Eye Research, 31:79–89, 2006 Prof. Kim, Y.S. /R3 Moon, Soo-youn Introduction • Diabetic retinopathy (DR) – Cause of blindness – Upregulation of vascular endothelial growth factor (VEGF), leukostasis and endothelin (ET) -1 • VEGF – Pivotal role in the pathogenesis of proliferative DR – Capillary nonperfusion, vascular permeability accentuation, and vascular proliferation • Leukostasis (leukocyte adhesion) – Important contributing factor to the pathogenesis of DR – Capillary obstruction – Intercellular adhesion molecule-1 (ICAM-1) • Takagi et al. – Upregulation of ET-1 in the streptozotocin (STZ)-induced diabetic rat retina - one of the factors to decrease the retinal blood flow in early DR • Objectives – Effect of ETA receptor antagonist (TA-0201; 1 mg/kg/day) on the expressions of VEGF and ICAM-1 in rat diabetic retina Materials and Methods • Animals and drug treatment – Male, 10-week-old, Sprague-Dawley rats – Single 70mg/kg IP injection of streptozotocin – Diabetic animals • ETA receptor selective antagonist (TA-0201; Tanabe Seiyaku Co., Ltd., Saitama, Japan) at a dose of 1 mg/kg/day for a total of 4 weeks (DM+TA-0201) • Vehicle group was treated with physiological saline only (DM+vehicle) – Non-DM control • Enzyme-linked immunosorbent assay for VEGF and ICAM-1 protein levels • • • • Immunohistochemistry – VEGF and ET-1 VEGF gene expression by rt-PCR First-strand cDNA synthesis Real-time PCR analysis – cDNA – VEGF/β-actin • Retinal leukostasis quantification – Fluorescein-isothiocyanate (FITC)-labeled concanavalin A lectin (ConA) (Vector Laboratories, Burlingame,CA,USA) • Histopathology examination • FITC-dextran angiography • Statistical analysis Results Characteristics of nondiabetic & diabetic rats Non-DM control DM+vehicle DM+TA-0201 Body weight (g) 496.4±51.2 345.1±35.1∗ 352.9±36.3∗ Blood glucose (mg/dl) 117.3±10.7 539.2±31.9† 528.7±39.0† Plasma insulin (ng/ml) 7.94±2.44 0.32±0.30 0.24±0.17 Values are means ± SD. Significantly different from non-DM control: ∗p<0.01 and †p<0.01. Expression of VEGF Gene expression and protein levels Immunohistochemical findings Expression of ET-1 Immunohistochemical findings Expression of ICAM-1 in retina and retinal leukostasis ICAM-1 protein levels Leukocyte adhesion in the retinal arterioles Fluorescence microscopic images Morphological and angiographic changes H&E stain & FITC-dextran angiography Conclusion • ETA receptor antagonist – useful in preventing the progression of diabetic retinopathy – suppressing the increase in VEGF and ICAM-1 levels as well as leukostasis in morphologically intact diabetic retina