Department of Ophthalmology, College of Medicine, Seoul National University & Seoul Artificial Eye Center Clinical Research Institute, Seoul National University Hospital, Seoul 151-744, Republic of Korea.
Am J Pathol. 2010 Mar;176(3):1517-24. doi: 10.2353/ajpath.2010.090398. Epub 2010 Jan 28.
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.
糖尿病性视网膜病变导致的视力丧失是由黄斑水肿引起的，其特征是血管通透性增加，这涉及到蛋白激酶 C（PKC）同工型的磷酸化激活。在此，我们证明 PKCδ抑制可预防糖尿病性视网膜病变中的血视网膜屏障破坏。糖尿病视网膜血管通透性增加伴随着封闭蛋白（ZO）-1 和 ZO-2 表达的减少。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，用罗特林、PKC-δ-DN 转染或 PKCδsiRNA 处理可有效恢复或预防血管渗漏以及视网膜血管上 ZO-1 和 ZO-2 的丢失。有趣的是，在晚期糖基化终产物处理的人视网膜微血管内皮细胞中，PKCδ从细胞质转位到膜上，这一过程被 PKCδ抑制所阻断。综上所述，PKCδ的激活与其亚细胞易位有关，参与了糖尿病引起的血管通透性，抑制 PKCδ可有效恢复视网膜血管中紧密连接蛋白的丢失。因此，我们认为抑制 PKCδ可能是治疗糖尿病性视网膜病变血视网膜屏障破坏的一种替代方法。
