Protection against methylglyoxal-derived AGEs by regulation of glyoxalase 1 prevents retinal neuroglial and vasodegenerative pathology
Protection against methylglyoxal-derived AGEs by regulation of glyoxalase 1 prevents retinal neuroglial and vasodegenerative pathology
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DOI：
10.1007/s00125-011-2393-0
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发表时间：
2012-03-01
期刊：
影响因子：
8.2
通讯作者：
Stitt, A. W.
中科院分区：
文献类型：
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作者：
Berner, A. K.;Brouwers, O.;Stitt, A. W.
甲基乙二醛(MG)是AGEs的重要前体。正常情况下，MG被乙醛酶(GLO)酶系统(包括组成酶GLO1和GLO2)解毒。糖尿病期间许多细胞糖酵解代谢增强可能超过解毒能力，并导致与年龄相关的病理。利用过表达GLO1的转基因大鼠模型，我们研究了该酶是否可以抑制视网膜AGE的形成和预防糖尿病视网膜病变的关键病变。用野生型(WT)和GLO1大鼠建立糖尿病模型，高血糖12周或24周后处死动物。采用免疫组织化学和超高效液相色谱-串联质谱仪(UPLC-MSMS)检测N(Epsilon)-(羧乙基)赖氨酸(CEL)、N(Epsilon)-(羧甲基)赖氨酸(CML)和MG-衍生咪唑酮-1(MG-H1)。通过胶质纤维酸性蛋白(GFAP)免疫反应和钾通道Kir4.1的空间定位来确定Muller胶质细胞功能障碍。与WT糖尿病患者相比，GLO1过度表达阻止了CEL和MG-H1在糖尿病视网膜中的积聚(p<；0.01)。在12周和24周的时间点，GLO1的过度表达(p<；0.05)显著地阻止了糖尿病相关的Muller胶质GFAP水平的增加和血管末端足部Kir4.1的丢失。在糖尿病24周时，GLO1糖尿病动物比WT糖尿病动物(P<；0.001)表现出更少的无细胞毛细血管。MG的解毒减少了AGE加合物的积累，这反过来可以防止随着糖尿病的进展而形成关键的视网膜神经胶质和血管病变。镁衍生的AGEs在糖尿病视网膜病变中起重要作用。
Methylglyoxal (MG) is an important precursor for AGEs. Normally, MG is detoxified by the glyoxalase (GLO) enzyme system (including component enzymes GLO1 and GLO2). Enhanced glycolytic metabolism in many cells during diabetes may overpower detoxification capacity and lead to AGE-related pathology. Using a transgenic rat model that overexpresses GLO1, we investigated if this enzyme can inhibit retinal AGE formation and prevent key lesions of diabetic retinopathy.Transgenic rats were developed by overexpression of full length GLO1. Diabetes was induced in wild-type (WT) and GLO1 rats and the animals were killed after 12 or 24 weeks of hyperglycaemia. N (epsilon)-(Carboxyethyl)lysine (CEL), N (epsilon)-(carboxymethyl)lysine (CML) and MG-derived-hydroimidazalone-1 (MG-H1) were determined by immunohistochemistry and by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MSMS). Muller glia dysfunction was determined by glial fibrillary acidic protein (GFAP) immunoreactivity and by spatial localisation of the potassium channel Kir4.1. Acellular capillaries were quantified in retinal flat mounts.GLO1 overexpression prevented CEL and MG-H1 accumulation in the diabetic retina when compared with WT diabetic counterparts (p < 0.01). Diabetes-related increases in Muller glial GFAP levels and loss of Kir4.1 at the vascular end-feet were significantly prevented by GLO1 overexpression (p < 0.05) at both 12- and 24-week time points. GLO1 diabetic animals showed fewer acellular capillaries than WT diabetic animals (p < 0.001) at 24 weeks' diabetes.Detoxification of MG reduces AGE adduct accumulation, which, in turn, can prevent formation of key retinal neuroglial and vascular lesions as diabetes progresses. MG-derived AGEs play an important role in diabetic retinopathy.