An Endothelin Type A Receptor Antagonist Reverses Upregulated VEGF and ICAM-1 Levels in Streptozotocin-Induced Diabetic Rat Retina

Abstract

Diabetic retinopathy, a cause of blindness, is often associated with the upregulation of vascular endothelial growth factor (VEGF) in the retina. Recently, leukocyte adhesion (leukostasis) is claimed for the occlusion of retinal capillary vascularity, which ultimately assists in the progression of diabetic retinopathy. In addition, intercellular adhesion molecule-1 (ICAM-1), a representative factor for leukostasis, is increased in diabetic retina. Endothelin (ET)-1, a potent vasoconstrictor peptide, is closely linked to the pathogenesis of diabetic retinopathy. Different therapeutic interventions concerning VEGF have already been proposed to prevent diabetic retinopathy. However, no study has yet reported concerning the effects of ET-1 receptor antagonist on the upregulated VEGF and ICAM-1 in morphologically intact diabetic retina. The current study investigated the effect of ET_A receptor antagonist (TA-0201; 1 mg kg⁻¹ day⁻¹) on the expressions of VEGF and ICAM-1 in rat diabetic retina. Diabetes was induced by intraperitoneal injection of streptozotocin (70 mg/kg) in Sprague-Dawley rats, whereas control rats (Cont) received only citrate buffer. After 1 week, the streptozotocin-administered rats were randomly divided into two groups: ET_A receptor antagonist-treated group (DM+TA-0201) and saline-treated group (DM+vehicle). After the treatment for 4 weeks, the retina was removed from the eyeball. In DM+vehicle group, the VEGF expression of retina was significantly increased (33.5 pg/mg) in comparison with that in the Cont group (25.1 pg/mg), and the upregulation of VEGF was reversed in DM+TA-0201 group (26.9 pg/mg), a phenomenon consistent with the change in VEGF mRNA levels. The expression of retinal ICAM-1 was increased in DM+vehicle group (55.1 pg/mg) compared with Cont group (43.8 pg/mg), and ET antagonism completely blocked this increase (43.8 pg/mg). Moreover, an increased leukostasis by 3.3-fold in DM+vehicle retina was returned to the control level by ET antagonism. In the current study, there was no obvious retinal morphological alteration from both the hematoxylin and eosin staining and the FITC-dextran angiography. Thus, ET_A receptor antagonist might be useful in preventing the progression of diabetic retinopathy, as evidenced by suppressing the increase in VEGF and ICAM-1 levels as well as leukostasis in morphologically intact diabetic retina.

KEYWORDS:

• diabetic retina
• endothelin antagonism
• ICAM-1
• leukostasis
• VEGF