Tan Adeline L Y, Forbes Josephine M, Cooper Mark E
Albert Einstein Centre for Diabetes Complications, Baker Heart Research Institute, St. Kilda Road, Central Melbourne, Victoria 8008, Australia.
Semin Nephrol. 2007 Mar;27(2):130-43. doi: 10.1016/j.semnephrol.2007.01.006.
Diabetic nephropathy is a major cause of morbidity and mortality in diabetic patients. Two key mechanisms implicated in the development of diabetic nephropathy include advanced glycation and oxidative stress. Advanced glycation is the irreversible attachment of reducing sugars onto amino groups of proteins to form advanced glycation end products (AGEs). AGE modification of proteins may lead to alterations in normal function by inducing cross-linking of extracellular matrices. Intracellular formation of AGEs also can cause generalized cellular dysfunction. Furthermore, AGEs can mediate their effects via specific receptors, such as the receptor for AGE (RAGE), activating diverse signal transduction cascades and downstream pathways, including generation of reactive oxygen species (ROS). Oxidative stress occurs as a result of the imbalance between ROS production and antioxidant defenses. Sources of ROS include the mitochondria, auto-oxidation of glucose, and enzymatic pathways including nicotinamide adenine dinucleotide phosphate reduced (NAD[P]H) oxidase. Beyond the current treatments to treat diabetic complications such as the optimization of blood pressure and glycemic control, it is predicted that new therapies designed to target AGEs, including AGE formation inhibitors and cross-link breakers, as well as targeting ROS using novel highly specific antioxidants, will become part of the treatment regimen for diabetic renal disease.
糖尿病肾病是糖尿病患者发病和死亡的主要原因。糖尿病肾病发生发展涉及的两个关键机制包括晚期糖基化和氧化应激。晚期糖基化是还原糖不可逆地附着在蛋白质的氨基上，形成晚期糖基化终末产物（AGEs）。蛋白质的AGE修饰可通过诱导细胞外基质交联导致正常功能改变。细胞内AGEs的形成也可导致广泛的细胞功能障碍。此外，AGEs可通过特定受体介导其作用，如AGE受体（RAGE），激活多种信号转导级联反应和下游通路，包括活性氧（ROS）的产生。氧化应激是ROS产生与抗氧化防御失衡的结果。ROS的来源包括线粒体、葡萄糖的自动氧化以及包括烟酰胺腺嘌呤二核苷酸磷酸还原酶（NAD[P]H）氧化酶在内的酶促途径。除了目前用于治疗糖尿病并发症的方法，如优化血压和血糖控制外，预计旨在靶向AGEs的新疗法，包括AGE形成抑制剂和交联破坏剂，以及使用新型高特异性抗氧化剂靶向ROS的疗法，将成为糖尿病肾病治疗方案的一部分。
