Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume 830-0011, Japan.
Pharmacol Res. 2012 Mar;65(3):297-302. doi: 10.1016/j.phrs.2011.11.001. Epub 2011 Nov 10.
Advanced glycation end products (AGEs) and their receptor (RAGE) axis contributes to diabetic nephropathy. An oral hypoglycemic agent, metformin may have a potential effect on the inhibition of glycation reactions. Further, since a pathophysiological crosstalk between renin-angiotensin system (RAS) and AGEs-RAGE axis is involved in diabetic nephropathy, it is conceivable that metformin and irbesartan additively could protect against the AGEs-RAGE-induced tubular cell injury. In this study, we addressed the issues. Metformin dose-dependently inhibited the formation of AGEs modification of bovine serum albumin (BSA). Compared with AGEs-modified BSA prepared without metformin (AGEs-MF0), those prepared in the presence of 30 mM or 100 mM metformin (AGEs-MF30 or AGEs-MF100) significantly reduced RAGE mRNA level, reactive oxygen species (ROS) generation, apoptosis, monocyte chemoattractant protein-1 and transforming growth factor-β mRNA level in tubular cells. Irbesartan further inhibited the harmful effects of AGEs-MF0 or AGEs-MF30 on tubular cells. Our present study suggests that combination therapy with metformin and irbesartan may have therapeutic potential in diabetic nephropathy; it could play a protective role against tubular injury in diabetes not only by inhibiting AGEs formation, but also by attenuating the deleterious effects of AGEs via down-regulating RAGE expression and subsequently suppressing ROS generation.
糖基化终产物（AGEs）及其受体（RAGE）轴促进糖尿病肾病的发生。一种口服降糖药二甲双胍可能对抑制糖基化反应有潜在作用。此外，由于肾素-血管紧张素系统（RAS）和 AGEs-RAGE 轴之间存在病理生理学的相互作用，二甲双胍和厄贝沙坦联合应用可能会对 AGEs-RAGE 诱导的肾小管细胞损伤起到保护作用。在本研究中，我们解决了这些问题。二甲双胍呈剂量依赖性地抑制牛血清白蛋白（BSA）的 AGEs 修饰形成。与没有二甲双胍（AGEs-MF0）制备的 AGEs 修饰 BSA 相比，用 30mM 或 100mM 二甲双胍（AGEs-MF30 或 AGEs-MF100）制备的 AGEs 修饰 BSA 显著降低了肾小管细胞的 RAGE mRNA 水平、活性氧（ROS）生成、细胞凋亡、单核细胞趋化蛋白-1 和转化生长因子-βmRNA 水平。厄贝沙坦进一步抑制了 AGEs-MF0 或 AGEs-MF30 对肾小管细胞的有害作用。本研究表明，二甲双胍和厄贝沙坦联合治疗可能对糖尿病肾病具有治疗潜力；它不仅可以通过抑制 AGEs 的形成，还可以通过下调 RAGE 表达，从而抑制 ROS 的产生，来发挥对糖尿病肾小管损伤的保护作用。
