Protective effects of the dipeptidyl peptidase IV inhibitor sitagliptin in the blood-retinal barrier in a type 2 diabetes animal model
Protective effects of the dipeptidyl peptidase IV inhibitor sitagliptin in the blood-retinal barrier in a type 2 diabetes animal model
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DOI：
10.1111/j.1463-1326.2011.01548.x
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发表时间：
2012-05-01
影响因子：
5.8
通讯作者：
Fernandes, R.
中科院分区：
文献类型：
--
作者：
Goncalves, A.;Leal, E.;Fernandes, R.
目的：本研究的目的是评估西他列汀，二肽基肽酶IV抑制剂（DPP-IV），在预防糖尿病对雄性Zucker糖尿病脂肪（ZDF）大鼠的血视网膜屏障的有害作用的有效性。方法：20周龄的ZDF大鼠用西他列汀（10 mg/kg/d）治疗6周。通过评价糖化血红蛋白（HbA 1c）评估药物对高血糖的影响。采用免疫印迹和/或免疫组织化学方法检测视网膜紧密连接蛋白（TJ）occludin和claudin-5、硝基酪氨酸残基、白细胞介素（IL）-1、BAX和Bcl-2的含量和/或分布。用末端脱氧核苷酸转移酶介导的dUTP缺口末端标记（TUNEL）法检测视网膜细胞凋亡。通过流式细胞术评估外周循环中存在的CD 34+细胞的数量，并通过免疫组化评估内皮祖细胞（EPC）粘附到视网膜vessels.Results的能力：西格列汀改善血液病控制所反映的HbA 1c水平显着下降约1.2%。西格列汀治疗可预防糖尿病诱导的TJ蛋白的内皮亚细胞分布变化。西格列汀还可降低糖尿病视网膜的亚硝化应激、炎症状态和细胞凋亡引起的细胞死亡。糖尿病动物外周血中CD 34+细胞水平降低，EPC与视网膜血管的粘附能力降低。西格列汀允许恢复的CD 34+细胞的数量存在于血流中的水平类似于他们的数量在控制和增加EPC的粘附能力的视网膜vessel.Conclusions：西格列汀防止亚硝化应激，炎症和视网膜细胞凋亡，并产生有益的影响，在ZDF大鼠视网膜的血视网膜屏障的完整性。
Aim: The aim of this study was to evaluate the efficacy of sitagliptin, a dipeptidyl peptidase IV inhibitor (DPP-IV), in preventing the deleterious effects of diabetes on the bloodretinal barrier in male Zucker Diabetic Fatty (ZDF) rats.Methods: ZDF rats at 20 weeks of age were treated with sitagliptin (10 mg/kg/day) during 6 weeks. The effect of the drug on glycaemia was assessed by evaluating glycated haemoglobin (HbA1c). The content and/or distribution of tight junction (TJ) proteins occludin and claudin-5, as well as nitrotyrosine residues, interleukin (IL)-1, BAX and Bcl-2 was evaluated in the retinas by western blotting and/or immunohistochemistry. Retinal cell apoptosis was assessed by the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling (TUNEL) assay. The number of CD34+ cells present in peripheral circulation was assessed by flow cytometry, and endothelial progenitor cells (EPC) adhesion ability to the retinal vessels was evaluated by immunohistochemistry.Results: Sitagliptin improved glycaemic control as reflected by a significant decrease in HbA1c levels by about 1.2%. Treatment with sitagliptin prevented the changes in the endothelial subcellular distribution of the TJ proteins induced by diabetes. Sitagliptin also decreased the nitrosative stress, the inflammatory state and cell death by apoptosis in diabetic retinas. Diabetic animals presented decreased levels of CD34+ cells in the peripheral circulation and decreased adhesion ability of EPC to the retinal vessels. Sitagliptin allowed a recovery of the number of CD34+ cells present in the bloodstream to levels similar to their number in controls and increased the adhesion ability of EPC to the retinal vessels.Conclusions: Sitagliptin prevented nitrosative stress, inflammation and apoptosis in retinal cells and exerted beneficial effects on the blood-retinal barrier integrity in ZDF rat retinas.