Abdo Shaaban, Zhang Shao-Ling, Chan John S D
Department of Medicine, University of Montreal and Research Center Hospital of QC, Canada.
J Diabetes Metab. 2015 May 10;6(6). doi: 10.4172/2155-6156.1000547.
Hyperglycemia, oxidative stress and renin-angiotensin system (RAS) dysfunction have been implicated in diabetic nephropathy (DN) progression, but the underlying molecular mechanisms are far from being fully understood. In addition to the systemic RAS, the existence of a local intrarenal RAS in renal proximal tubular cells has been recognized. Angiotensinogen is the sole precursor of all angiotensins (Ang). Intrarenal reactive oxygen species (ROS) generation, Ang II level and RAS gene expression are up-regulated in diabetes, indicating that intrarenal ROS and RAS activation play an important role in DN. The nuclear factor erythroid 2-related factor 2 (Nrf2)-Kelch-like ECH-associated protein 1 (Keap1) pathway is one of the major protective processes that occurs in response to intracellular oxidative stress. Nrf2 stimulates an array of antioxidant enzymes that convert excessive ROS to less reactive or less damaging forms. Recent studies have, however, revealed that Nrf2 activation might have other undesirable effects in diabetic animals and in diabetic patients with chronic kidney disease. This mini-review summarizes current knowledge of the relationship between ROS, Nrf2 and intra renal RAS activation in DN progression as well as possible novel target(s) for DN treatment.
高血糖、氧化应激和肾素-血管紧张素系统（RAS）功能障碍与糖尿病肾病（DN）的进展有关，但其潜在的分子机制尚未完全清楚。除了全身RAS外，肾近端小管细胞中存在局部肾内RAS已得到认可。血管紧张素原是所有血管紧张素（Ang）的唯一前体。糖尿病时肾内活性氧（ROS）生成、Ang II水平和RAS基因表达上调，表明肾内ROS和RAS激活在DN中起重要作用。核因子红细胞2相关因子2（Nrf2）- Kelch样ECH相关蛋白1（Keap1）途径是细胞内氧化应激反应中发生的主要保护过程之一。Nrf2刺激一系列抗氧化酶，将过量的ROS转化为活性较低或损伤较小的形式。然而，最近的研究表明，Nrf2激活在糖尿病动物和患有慢性肾病的糖尿病患者中可能有其他不良影响。本综述总结了目前关于ROS、Nrf2与肾内RAS激活在DN进展中的关系以及DN治疗可能的新靶点的知识。
