Endothelin Receptor-A Antagonist Attenuates Retinal Vascular and Neuroretinal Pathology in Diabetic Mice
Endothelin Receptor-A Antagonist Attenuates Retinal Vascular and Neuroretinal Pathology in Diabetic Mice
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DOI：
10.1167/iovs.13-13676
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发表时间：
2014-04-01
影响因子：
4.4
通讯作者：
Fawzi, Amani A.
中科院分区：
文献类型：
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作者：
Chou, Jonathan C.;Rollins, Stuart D.;Fawzi, Amani A.
目的.我们试图确定阿曲生坦（一种选择性内皮素A受体拮抗剂）对db/db小鼠（2型糖尿病和糖尿病视网膜病的动物模型）视网膜血管和结构完整性的影响。方法。给予23周龄的糖尿病小鼠阿曲生坦或赋形剂在饮用水中的治疗8周。在治疗期结束时，对眼睛进行胰蛋白酶消化，以评估视网膜血管病理学，重点是毛细血管变性、内皮细胞和周细胞损失。用石蜡包埋的视网膜横截面评估视神经附近和视网膜周边的视网膜亚层厚度。免疫组化和TUNEL法检测视网膜细胞和血管增生。与未治疗的db/db小鼠相比，阿曲生坦治疗能够通过减少周细胞损失来改善视网膜血管病理学（分别为29.2% +/- 0.4% vs. 44.4% +/-2.0%，P < 0.05）和毛细血管变性（通过无细胞毛细血管百分比测定）（分别为8.6% +/- 0.3%对3.3% +/-0.41%，P < 0.05）。与未处理的db/db小鼠相比，在用阿曲生坦处理的db/db小鼠中也观察到在经处理的糖尿病小鼠中在视神经处和在外周处的内部视网膜变薄的减少（P < 0.05）。TUNEL法提示阿曲生坦可降低db/db小鼠视网膜神经层和血管周细胞的凋亡。使用阿曲生坦的内皮素-A受体阻断剂显著减少糖尿病小鼠中的血管和神经视网膜并发症。内皮素-A受体阻断剂是糖尿病视网膜病变的一个有前途的治疗靶点。
PURPOSE. We sought to determine the effects of atrasentan, a selective endothelin-A receptor antagonist, on the retinal vascular and structural integrity in a db/db mouse, an animal model of type 2 diabetes and diabetic retinopathy.METHODS. Diabetic mice, 23 weeks old, were given either atrasentan or vehicle treatment in drinking water for 8 weeks. At the end of the treatment period, eyes underwent trypsin digest to assess the retinal vascular pathology focusing on capillary degeneration, endothelial cell, and pericyte loss. Paraffin-embedded retinal cross sections were used to evaluate retinal sublayer thickness both near the optic nerve and in the retinal periphery. Immunohistochemistry and TUNEL assay were done to evaluate retinal cellular and vascular apoptosis.RESULTS. Compared with untreated db/db mice, atrasentan treatment was able to ameliorate the retinal vascular pathology by reducing pericyte loss (29.2% +/- 0.4% vs. 44.4% +/- 2.0%, respectively, P < 0.05) and capillary degeneration as determined by the percentage of acellular capillaries (8.6% +/- 0.3% vs. 3.3% +/- 0.41%, respectively, P < 0.05). A reduction in inner retinal thinning both at the optic nerve and at the periphery in treated diabetic mice was also observed in db/db mice treated with atrasentan as compared with untreated db/db mice (P < 0.05). TUNEL assay suggested that atrasentan may decrease enhanced apoptosis in neuroretinal layers and vascular pericytes in the db/db mice.CONCLUSIONS. Endothelin-A receptor blockade using atrasentan significantly reduces the vascular and neuroretinal complications in diabetic mice. Endothelin-A receptor blockade is a promising therapeutic target in diabetic retinopathy.