Inhibition of Protein Kinase C δ Attenuates Blood-Retinal Barrier Breakdown in Diabetic Retinopathy
Inhibition of Protein Kinase C δ Attenuates Blood-Retinal Barrier Breakdown in Diabetic Retinopathy
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DOI：
10.2353/ajpath.2010.090398
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发表时间：
2010-03-01
影响因子：
6
通讯作者：
Kim, Kyu-Won
中科院分区：
文献类型：
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作者：
Kim, Jeong-Hun;Kim, Jin Hyoung;Kim, Kyu-Won
糖尿病视网膜病变的视力丧失是由于黄斑水肿，其特征是血管通透性增加，这涉及与蛋白激酶C(PKC)亚型激活相关的磷酸化。在这里，我们证明了抑制PKC Delta可以预防糖尿病视网膜病变中血-视网膜屏障的破坏。糖尿病视网膜血管通透性增加的同时伴有闭锁带(ZO)-1和ZO-2表达的降低。在糖尿病视网膜和晚期糖基化终产物处理的人视网膜微血管内皮细胞中，rotlerin、PKC-Delta-dN或PKC Delta的siRNA可有效地恢复或防止视网膜血管上ZO-1和ZO-2的血管渗漏和丢失。有趣的是，PKC三角洲移位了。晚期糖基化终产物处理的人视网膜微血管内皮细胞从胞浆到细胞膜，其被PKC Delta抑制所阻断。综上所述，PKC Delta的激活与其亚细胞转位有关，参与了糖尿病反应中的血管通透性，抑制PKC Delta可有效恢复视网膜血管中紧密连接蛋白的丢失。因此，我们建议抑制PKC Delta可作为糖尿病视网膜病变血-视网膜屏障破坏的替代治疗。(Am J Pathol2010,176：1517-1524；DOI：10.2353/ajpath.2010.090.398)
Vision loss in diabetic retinopathy is due to macular edema characterized by increased vascular permeability, which involves phosphorylation associated with activation of protein kinase C (PKC) isoforms. Herein, we demonstrated PKC delta inhibition could prevent blood-retinal barrier breakdown in diabetic retinopathy. increased vascular permeability of diabetic retina was accompanied by a decrease of zonula occludens (ZO)-1 and ZO-2 expression. In diabetic retina and advanced glycation end product-treated human retinal microvascular endothelial cells, vascular leakage and loss of ZO-1 and ZO-2 on retinal vessels were effectively restored or prevented with treatment of rottlerin, transfection of PKC-delta-DN, or siRNA for PKC delta. Interestingly, PKC delta translocated. from cytosol to membrane in advanced glycation end product-treated human retinal microvascular endothelial cells, which was blocked by PKC delta inhibition. Taken together, PKC delta activation, related to its subcellular translocation, is involved in vascular permeability in response to diabetes, and inhibition of PKC delta effectively restores loss of tight junction proteins in retinal vessels. Therefore, we suggest that inhibition of PKC delta could be an alternative treatment to blood-retinal barrier breakdown in diabetic retinopathy. (Am J Pathol 2010, 176:1517-1524; DOI: 10.2353/ajpath.2010.090.398)