Glyoxalase-1 overexpression reduces endothelial dysfunction and attenuates early renal impairment in a rat model of diabetes
Glyoxalase-1 overexpression reduces endothelial dysfunction and attenuates early renal impairment in a rat model of diabetes
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DOI：
10.1007/s00125-013-3088-5
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发表时间：
2014-01-01
期刊：
影响因子：
8.2
通讯作者：
Schalkwijk, Casper G.
中科院分区：
文献类型：
--
作者：
Brouwers, Olaf;Niessen, Petra M. G.;Schalkwijk, Casper G.
目的/假设在糖尿病中，晚期糖基化终产物（AGEs）和AGE前体甲基乙二醛（MGO）与内皮功能障碍和微血管并发症的发生相关。在这项研究中，我们使用的糖尿病大鼠模型，其中大鼠转基因过表达的MGO-解毒酶-I（GLO-I），以确定细胞内糖化对血管功能和早期肾脏的发展的影响diabetes.Methods野生型和Glo 1-overexpressing大鼠糖尿病的一段时间为24周的静脉注射链脲佐菌素。分离肠系膜动脉以用钢丝肌描记器研究离体血管反应性，并处理肾脏进行组织学检查。通过质谱和免疫组织化学测定糖基化。炎症，内皮功能障碍和肾功能障碍的标志物进行了测定与ELISA为基础的techniques.Results糖尿病诱导的形成AGEs在肠系膜动脉和内皮功能障碍减少Glo 1过表达。尽管没有晚期肾病病变，但Glo 1过表达减弱了肾功能不全的早期标志物（即肾小球体积增加，足细胞数量减少和糖尿病诱导的尿标志物白蛋白，骨桥蛋白，肾脏炎症分子-1和nephrin升高）。与此一致，在培养的内皮细胞中Glo 1的下调导致炎症和内皮功能障碍标志物的表达增加。在完全分化培养的足细胞孵育MGO导致apoptosis. Conclusion/interpretation本研究表明，有效调节的GLO-I酶是重要的，在预防血管细胞内糖化，内皮功能障碍和早期肾功能损害的实验性糖尿病。因此，调节GLO-I通路可能提供一种预防糖尿病血管并发症的新方法。
Aims/hypothesis In diabetes, advanced glycation end-products (AGEs) and the AGE precursor methylglyoxal (MGO) are associated with endothelial dysfunction and the development of microvascular complications. In this study we used a rat model of diabetes, in which rats transgenically overexpressed the MGO-detoxifying enzyme glyoxalase-I (GLO-I), to determine the impact of intracellular glycation on vascular function and the development of early renal changes in diabetes.Methods Wild-type and Glo1-overexpressing rats were rendered diabetic for a period of 24 weeks by intravenous injection of streptozotocin. Mesenteric arteries were isolated to study ex vivo vascular reactivity with a wire myograph and kidneys were processed for histological examination. Glycation was determined by mass spectrometry and immunohistochemistry. Markers for inflammation, endothelium dysfunction and renal dysfunction were measured with ELISA-based techniques.Results Diabetes-induced formation of AGEs in mesenteric arteries and endothelial dysfunction were reduced by Glo1 overexpression. Despite the absence of advanced nephrotic lesions, early markers of renal dysfunction (i.e. increased glomerular volume, decreased podocyte number and diabetes-induced elevation of urinary markers albumin, osteopontin, kidney-inflammation-molecule-1 and nephrin) were attenuated by Glo1 overexpression. In line with this, downregulation of Glo1 in cultured endothelial cells resulted in increased expression of inflammation and endothelium dysfunction markers. In fully differentiated cultured podocytes incubation with MGO resulted in apoptosis.Conclusions/interpretation This study shows that effective regulation of the GLO-I enzyme is important in the prevention of vascular intracellular glycation, endothelial dysfunction and early renal impairment in experimental diabetes. Modulating the GLO-I pathway therefore may provide a novel approach to prevent vascular complications in diabetes.