An endothelin type A receptor antagonist reverses upregulated VEGF and ICAM-1 levels in streptozotocin-induced diabetic rat retina
An endothelin type A receptor antagonist reverses upregulated VEGF and ICAM-1 levels in streptozotocin-induced diabetic rat retina
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DOI：
10.1080/02713680500478923
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发表时间：
2006-01-01
影响因子：
2
通讯作者：
Hori, S
中科院分区：
文献类型：
--
作者：
Masuzawa, K;Goto, K;Hori, S
糖尿病视网膜病变是导致失明的原因之一，通常与视网膜中血管内皮生长因子 (VEGF) 的上调有关。最近，白细胞粘附（白细胞停滞）被认为是视网膜毛细血管闭塞的原因，这最终有助于糖尿病视网膜病变的进展。此外，白细胞停滞的代表性因子——细胞间粘附分子-1（ICAM-1）在糖尿病视网膜中增加。内皮素 (ET)-1 是一种有效的血管收缩肽，与糖尿病视网膜病变的发病机制密切相关。已经提出了有关 VEGF 的不同治疗干预措施来预防糖尿病视网膜病变。然而，尚未有研究报道ET-1受体拮抗剂对形态完整的糖尿病视网膜中上调的VEGF和ICAM-1的影响。本研究探讨ETA受体拮抗剂TA-0201；1 mg·kg(-1)·day(-1))对糖尿病大鼠视网膜VEGF和ICAM-I表达的影响。在 Sprague-Dawley 大鼠中腹腔注射链脲佐菌素 (70 mg/kg) 诱导糖尿病，而对照大鼠 (Cont) 仅接受柠檬酸盐缓冲液。 I周后，将链脲佐菌素给药的大鼠随机分为两组：ETA受体拮抗剂治疗组(DM+TA-0201)和盐水治疗组(DM+载体)。治疗4周后，将视网膜从眼球上摘除。与Cont组（25.1 pg/mg）相比，DM+vehicle组视网膜VEGF表达显着增加（33.5 pg/mg），而DM+TA-0201组（26.9 pg/mg）VEGF的上调被逆转，这一现象与VEGF mRNA水平的变化一致。与Cont组(43.8pg/mg)相比，DM+载体组中视网膜ICAM-I的表达增加(55.1pg/mg)，而ET拮抗剂完全阻断了这种增加(43.8pg/mg)。此外，DM+载体视网膜中白细胞停滞增加3.3倍，通过ET拮抗作用恢复到对照水平。在本研究中，苏木精和伊红染色以及FITC-葡聚糖血管造影均未发现明显的视网膜形态学改变。因此，ETA 受体拮抗剂可能有助于预防糖尿病视网膜病变的进展，这通过抑制 VEGF 和 ICAM-1 水平的增加以及形态完整的糖尿病视网膜中的白细胞停滞来证明。
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 retina] 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-I receptor antagonist on the upregulated VEGF and ICAM-1 in morphologically intact diabetic retina. The current study investigated the effect of ETA receptor antagonist (TA-0201; 1 mg kg(-1) day(-1)) on the expressions of VEGF and ICAM-I 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 I week, the streptozotocin-administered rats were randomly divided into two groups: ETA 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-I 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, ETA 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.