Warwick Medical School, Clinical Sciences Research Laboratories, University of Warwick, University Hospital, Coventry, UK.
Warwick Medical School, Clinical Sciences Research Laboratories, University of Warwick, University Hospital, Coventry, UK.
Kidney Int. 2018 Apr;93(4):803-813. doi: 10.1016/j.kint.2017.11.034. Epub 2018 Feb 22.
Advanced glycation end products (AGEs) are stable posttranslational modifications of proteins formed by the spontaneous reaction with glucose and related metabolites. Important AGEs quantitatively are methylglyoxal (MG)-derived hydroimidazolone MG-H1, N-carboxymethyl-lysine (CML), and glucosepane. They contribute to the development of chronic kidney disease (CKD). Cellular proteolysis of AGE-modified proteins forms AGE free adducts, glycated amino acids, which are cleared by the kidneys and excreted in urine. Dietary AGEs mainly supplement the endogenous flux of AGE free adduct formation. AGE free adducts accumulate markedly in plasma with decline in glomerular filtration rate. A key precursor of AGEs is the dicarbonyl metabolite MG, which is metabolized by glyoxalase 1 (Glo1) of the cytoplasmic glyoxalase system. Proteins susceptible to MG modification are collectively called the dicarbonyl proteome. Abnormal increase of MG dicarbonyl stress is a characteristic of CKD, driven by down-regulation of renal Glo1, increasing flux of MG-H1 formation. Protein inactivation and dysfunction linked to the dicarbonyl proteome contributes to CKD development. The receptor for AGEs, RAGE, is important in development of CKD, but its interaction with AGEs in vivo remains enigmatic; other ligands and ternary complexation may be influential. Prevention of diabetic kidney disease (DKD) by overexpression of Glo1 in transgenic animal models has stimulated the development of small-molecule inducers of Glo1 expression, Glo1 inducers, to prevent AGE formation. trans-Resveratrol-hesperetin combination therapy is a Glo1 inducer. In clinical trial it demonstrated a profound improvement in insulin resistance and vascular inflammation. It may find future therapeutic application for treatment of DKD.
晚期糖基化终产物（AGEs）是蛋白质在葡萄糖和相关代谢物的自发反应下形成的稳定的翻译后修饰物。重要的 AGEs 包括甲基乙二醛（MG）衍生的羟咪唑啉 MG-H1、N-羧甲基赖氨酸（CML）和葡萄糖肽。它们有助于慢性肾脏病（CKD）的发展。AGE 修饰蛋白的细胞蛋白水解形成 AGE 游离加合物，糖化氨基酸，这些物质被肾脏清除并在尿液中排泄。饮食中的 AGE 主要补充内源性 AGE 游离加合物形成的通量。AGE 游离加合物在肾小球滤过率下降时在血浆中明显积累。AGE 的关键前体是二羰基代谢物 MG，它由细胞质糖醛酸酶系统中的糖醛酸酶 1（Glo1）代谢。易受 MG 修饰的蛋白质统称为二羰基蛋白质组。MG 二羰基应激的异常增加是 CKD 的一个特征，这是由肾脏 Glo1 下调驱动的，MG-H1 形成的通量增加。与二羰基蛋白质组相关的蛋白质失活和功能障碍导致 CKD 的发展。AGE 的受体 RAGE 在 CKD 的发展中很重要，但它与体内 AGEs 的相互作用仍然是一个谜；其他配体和三元复合物可能具有影响力。在转基因动物模型中过表达 Glo1 预防糖尿病肾病（DKD）刺激了 Glo1 表达的小分子诱导剂的开发，即 Glo1 诱导剂，以防止 AGE 形成。反式白藜芦醇-橙皮苷联合治疗是一种 Glo1 诱导剂。在临床试验中，它显著改善了胰岛素抵抗和血管炎症。它可能会在未来的 DKD 治疗中找到应用。
