Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, 67 Asahi-machi, Kurume, 830-0011, Japan.
Microvasc Res. 2010 Sep;80(2):227-32. doi: 10.1016/j.mvr.2010.03.015. Epub 2010 Apr 8.
Advanced glycation end products (AGE), senescent macroprotein derivatives formed at an accelerated rate under hyperglycemic conditions, elicit oxidative stress generation and inflammatory reactions, thus being involved in the development and progression of diabetic nephropathy. Recently, we, along with others, have found that pigment epithelium-derived factor (PEDF), a glycoprotein with potent neuronal differentiating activity, inhibits AGE-elicited endothelial cell damage through its anti-oxidative properties and blocks the progression of experimental diabetic retinopathy. However, a role of PEDF in diabetic nephropathy is not fully understood. In this study, we investigated whether and how PEDF could protect against AGE-elicited mesangial cell damage in vitro. PEDF mRNA and protein levels were decreased by the treatments of AGE. PEDF or neutralizing antibody raised against RAGE (receptor for AGE) was found to inhibit the AGE-induced oxidative stress generation and subsequent NF-kappaB activation in mesangial cells. Further, AGE increased mRNA levels of monocyte chemoattractant protein-1 (MCP-1), vascular cell adhesion molecule-1 (VCAM-1) and plasminogen activator inhibitor-1 (PAI-1) in mesangial cells, all of which were prevented by the treatments with PEDF, RAGE antibody or pyrrolidine dithiocarbamate, a NF-kappaB inhibitor. The present results demonstrated for the first time that PEDF blocked the AGE-RAGE-mediated mesangial cell injury by inhibiting NF-kappaB activation via suppression of reactive oxygen species generation. Our present study suggests that substitution of PEDF proteins may be a promising strategy for the treatment of diabetic nephropathy.
糖基化终产物（AGE）是在高血糖条件下加速形成的衰老的大分子蛋白衍生物，它会引发氧化应激和炎症反应，从而参与糖尿病肾病的发生和发展。最近，我们与其他人一起发现，色素上皮衍生因子（PEDF）是一种具有强大神经元分化活性的糖蛋白，通过其抗氧化特性抑制 AGE 诱导的内皮细胞损伤，并阻止实验性糖尿病视网膜病变的进展。然而，PEDF 在糖尿病肾病中的作用尚未完全阐明。在这项研究中，我们研究了 PEDF 是否以及如何在体外保护肾小球系膜细胞免受 AGE 诱导的损伤。AGE 的处理降低了 PEDF mRNA 和蛋白水平。发现 PEDF 或针对 RAGE（AGE 受体）的中和抗体可抑制系膜细胞中 AGE 诱导的氧化应激产生和随后的 NF-κB 激活。此外，AGE 增加了系膜细胞中单核细胞趋化蛋白-1（MCP-1）、血管细胞黏附分子-1（VCAM-1）和纤溶酶原激活物抑制剂-1（PAI-1）的 mRNA 水平，这些水平都可以通过 PEDF、RAGE 抗体或吡咯烷二硫代氨基甲酸盐（NF-κB 抑制剂）的处理来预防。这些结果首次表明，PEDF 通过抑制活性氧的产生来抑制 NF-κB 激活，从而阻断 AGE-RAGE 介导的系膜细胞损伤。我们的研究表明，替代 PEDF 蛋白可能是治疗糖尿病肾病的一种有前途的策略。
