当前位置: X-MOL 学术Nature › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Inhibition of soluble epoxide hydrolase prevents diabetic retinopathy
Nature ( IF 50.5 ) Pub Date : 2017-12-01 , DOI: 10.1038/nature25013
Jiong Hu 1, 2 , Sarah Dziumbla 1, 2 , Jihong Lin 3 , Sofia-Iris Bibli 1, 2 , Sven Zukunft 1 , Julian de Mos 4 , Khader Awwad 1 , Timo Frömel 1, 2 , Andreas Jungmann 5, 6 , Kavi Devraj 7 , Zhixing Cheng 8 , Liya Wang 8 , Sascha Fauser 9 , Charles G Eberhart 10 , Akrit Sodhi 10 , Bruce D Hammock 11 , Stefan Liebner 2, 7 , Oliver J Müller 5, 6, 12 , Clemens Glaubitz 4 , Hans-Peter Hammes 3 , Rüdiger Popp 1, 2 , Ingrid Fleming 1, 2
Affiliation  

Diabetic retinopathy is an important cause of blindness in adults, and is characterized by progressive loss of vascular cells and slow dissolution of inter-vascular junctions, which result in vascular leakage and retinal oedema. Later stages of the disease are characterized by inflammatory cell infiltration, tissue destruction and neovascularization. Here we identify soluble epoxide hydrolase (sEH) as a key enzyme that initiates pericyte loss and breakdown of endothelial barrier function by generating the diol 19,20-dihydroxydocosapentaenoic acid, derived from docosahexaenoic acid. The expression of sEH and the accumulation of 19,20-dihydroxydocosapentaenoic acid were increased in diabetic mouse retinas and in the retinas and vitreous humour of patients with diabetes. Mechanistically, the diol targeted the cell membrane to alter the localization of cholesterol-binding proteins, and prevented the association of presenilin 1 with N-cadherin and VE-cadherin, thereby compromising pericyte–endothelial cell interactions and inter-endothelial cell junctions. Treating diabetic mice with a specific sEH inhibitor prevented the pericyte loss and vascular permeability that are characteristic of non-proliferative diabetic retinopathy. Conversely, overexpression of sEH in the retinal Müller glial cells of non-diabetic mice resulted in similar vessel abnormalities to those seen in diabetic mice with retinopathy. Thus, increased expression of sEH is a key determinant in the pathogenesis of diabetic retinopathy, and inhibition of sEH can prevent progression of the disease.

中文翻译:

抑制可溶性环氧化物水解酶可预防糖尿病性视网膜病变

糖尿病视网膜病变是成人失明的重要原因,其特征是血管细胞进行性丢失和血管间连接处溶解缓慢,从而导致血管渗漏和视网膜水肿。疾病后期的特征是炎性细胞浸润、组织破坏和新血管形成。在这里,我们将可溶性环氧化物水解酶 (sEH) 鉴定为一种关键酶,它通过产生源自二十二碳六烯酸的二醇 19,20-二羟基二十二碳五烯酸来启动周细胞损失和内皮屏障功能的破坏。sEH 的表达和 19,20-二羟基二十二碳五烯酸的积累在糖尿病小鼠视网膜以及糖尿病患者的视网膜和玻璃体液中增加。从机械上讲,二醇靶向细胞膜以改变胆固醇结合蛋白的定位,并阻止早老素 1 与 N-钙粘蛋白和 VE-钙粘蛋白结合,从而损害周细胞-内皮细胞相互作用和内皮细胞间连接。用特定的 sEH 抑制剂治疗糖尿病小鼠可防止非增殖性糖尿病视网膜病变的特征性周细胞丢失和血管通透性。相反,非糖尿病小鼠视网膜 Müller 神经胶质细胞中 sEH 的过度表达会导致与患有视网膜病变的糖尿病小鼠相似的血管异常。因此,sEH 表达的增加是糖尿病视网膜病变发病机制的关键决定因素,抑制 sEH 可以阻止疾病的进展。并阻止早老素 1 与 N-钙粘蛋白和 VE-钙粘蛋白结合,从而损害周细胞-内皮细胞相互作用和内皮细胞间连接。用特定的 sEH 抑制剂治疗糖尿病小鼠可防止非增殖性糖尿病视网膜病变的特征性周细胞丢失和血管通透性。相反,非糖尿病小鼠视网膜 Müller 神经胶质细胞中 sEH 的过度表达会导致与患有视网膜病变的糖尿病小鼠相似的血管异常。因此,sEH 表达的增加是糖尿病视网膜病变发病机制的关键决定因素,抑制 sEH 可以阻止疾病的进展。并阻止早老素 1 与 N-钙粘蛋白和 VE-钙粘蛋白结合,从而损害周细胞-内皮细胞相互作用和内皮细胞间连接。用特定的 sEH 抑制剂治疗糖尿病小鼠可防止非增殖性糖尿病视网膜病变的特征性周细胞丢失和血管通透性。相反,非糖尿病小鼠视网膜 Müller 神经胶质细胞中 sEH 的过度表达会导致与患有视网膜病变的糖尿病小鼠相似的血管异常。因此,sEH 表达的增加是糖尿病视网膜病变发病机制的关键决定因素,抑制 sEH 可以阻止疾病的进展。用特定的 sEH 抑制剂治疗糖尿病小鼠可防止非增殖性糖尿病视网膜病变的特征性周细胞丢失和血管通透性。相反,非糖尿病小鼠视网膜 Müller 神经胶质细胞中 sEH 的过度表达会导致与患有视网膜病变的糖尿病小鼠相似的血管异常。因此,sEH 表达的增加是糖尿病视网膜病变发病机制的关键决定因素,抑制 sEH 可以阻止疾病的进展。用特定的 sEH 抑制剂治疗糖尿病小鼠可防止非增殖性糖尿病视网膜病变的特征性周细胞丢失和血管通透性。相反,非糖尿病小鼠视网膜 Müller 神经胶质细胞中 sEH 的过度表达会导致与患有视网膜病变的糖尿病小鼠相似的血管异常。因此,sEH 表达的增加是糖尿病视网膜病变发病机制的关键决定因素,抑制 sEH 可以阻止疾病的进展。
更新日期:2017-12-01
down
wechat
bug