Yamagishi Sho-ichi, Nakamura Kazuo, Matsui Takanori, Noda Yoshihiro, Imaizumi Tsutomu
Division of Cardiovascular Medicine, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan.
Curr Pharm Des. 2008;14(5):487-95. doi: 10.2174/138161208783597416.
Diabetic vascular complication is a leading cause of acquired blindness, end-stage renal failure, a variety of neuropathies and accelerated atherosclerosis, which could account for disabilities and high mortality rates in patients with diabetes. Although several hyperglycemia-elicited metabolic and hemodynamic derangements have been implicated in the pathogenesis of diabetic vascular complication, the process of formation and accumulation of advanced glycation end products (AGEs) and their mode of action are most compatible with the theory 'hyperglycemic memory'. Further, there is a growing body of evidence that AGEs and their receptor (RAGE) axis is involved in the pathogenesis of diabetic vascular complication. Indeed, the engagement of RAGE with AGEs is shown to elicit oxidative stress generation and subsequently evoke inflammatory responses in various types of cells, thus playing an important role in the development and progression of diabetic micro- and macroangiopathy. These observations suggest that down-regulation of RAGE expression or blockade of the RAGE downstream signaling may be a promising target for therapeutic intervention in diabetic vascular complication. In this review, we discuss several types of agents that could potentially inhibit RAGE expression or its downstream pathways and their therapeutic implications in diabetic vascular complication.
糖尿病血管并发症是导致后天性失明、终末期肾衰竭、多种神经病变以及加速动脉粥样硬化的主要原因，这些并发症可导致糖尿病患者残疾和高死亡率。尽管几种由高血糖引发的代谢和血流动力学紊乱与糖尿病血管并发症的发病机制有关，但晚期糖基化终产物（AGEs）的形成和积累过程及其作用方式与“高血糖记忆”理论最为相符。此外，越来越多的证据表明，AGEs及其受体（RAGE）轴参与了糖尿病血管并发症的发病机制。事实上，RAGE与AGEs的结合可引发氧化应激的产生，并随后在各种类型的细胞中引发炎症反应，从而在糖尿病微血管和大血管病变的发生和发展中发挥重要作用。这些观察结果表明，下调RAGE表达或阻断RAGE下游信号可能是糖尿病血管并发症治疗干预的一个有前景的靶点。在这篇综述中，我们讨论了几种可能抑制RAGE表达或其下游途径的药物及其在糖尿病血管并发症中的治疗意义。
