Inagi Reiko, Nangaku Masaomi, Miyata Toshio
Institute of Medical Sciences, Tokai University School of Medicine, Kanagawa 259-1193, Japan.
Ann N Y Acad Sci. 2005 Jun;1043:605-8. doi: 10.1196/annals.1338.068.
Diabetic nephropathy is the most common cause of end-stage renal failure. The primary glomerular changes in diabetic nephropathy are diffuse and nodular glomerulosclerosis, manifested by an increase in mesangial matrix. Research has demonstrated that advanced glycation end products (AGEs), oxidative stress, and carbonyl stress might play a crucial role in the pathogenesis of diabetic nephropathy via multiple mechanisms. AGEs augment extracellular matrix synthesis, contribute to the release of proinflammatory cytokines and expression of growth factors and adhesion molecules, and interact with the renin-angiotensin system. Megsin is a novel serine protease inhibitor predominantly expressed in mesanguim. Megsin is upregulated in kidney samples of patients with diabetic nephropathy. Transgenic mice overexpressing megsin spontaneously develop kidney disease characterized by mesangial injury. Megsin is likely to contribute to mesangial injury in the process of diabetic nephropathy. Lack of appropriate animal models has hampered understanding the pathogenesis of diabetic nephropathy and development of effective therapies. Megsin and AGEs are suitable targets for new drugs of diabetic nephropathy and for the development of appropriate animal models of diabetic nephropathy.
糖尿病肾病是终末期肾衰竭最常见的病因。糖尿病肾病的主要肾小球改变是弥漫性和结节性肾小球硬化，表现为系膜基质增加。研究表明，晚期糖基化终末产物（AGEs）、氧化应激和羰基应激可能通过多种机制在糖尿病肾病的发病机制中起关键作用。AGEs增加细胞外基质合成，促进促炎细胞因子的释放以及生长因子和黏附分子的表达，并与肾素-血管紧张素系统相互作用。Megsin是一种主要在系膜中表达的新型丝氨酸蛋白酶抑制剂。在糖尿病肾病患者的肾脏样本中，Megsin表达上调。过表达Megsin的转基因小鼠会自发发展出以系膜损伤为特征的肾脏疾病。Megsin可能在糖尿病肾病过程中导致系膜损伤。缺乏合适的动物模型阻碍了对糖尿病肾病发病机制的理解以及有效治疗方法的开发。Megsin和AGEs是糖尿病肾病新药以及开发合适的糖尿病肾病动物模型的合适靶点。
