Center for Translational and Advanced Research, Tohoku University Graduate School of Medicine, 2-1 Seiryo-Machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan.
Nat Rev Nephrol. 2010 Feb;6(2):83-95. doi: 10.1038/nrneph.2009.211. Epub 2009 Dec 15.
Chronic hypoxia induces sequential abnormalities in oxygen metabolism (for example, oxidative stress, nitrosative stress, advanced glycation, carbonyl stress, endoplasmic reticulum stress) in the kidneys of individuals with diabetes. Identification of these abnormalities improves our understanding of therapeutic benefits that can be achieved with antihypertensive agents, the control of hyperglycemia and/or hyperinsulinemia and the dietary correction of obesity. Key to the body's defense against hypoxia is hypoxia-inducible factor, the activity of which is modulated by prolyl hydroxylases (PHDs)-oxygen sensors whose inhibition may prove therapeutic. Renal benefits of small-molecule PHD inhibitors have been documented in several animal models, including those of diabetic nephropathy. Three different PHD isoforms have been identified (PHD1, PHD2 and PHD3) and their respective roles have been delineated in knockout mouse studies. Unfortunately, none of the current inhibitors is specific for a distinct PHD isoform. Nonspecific inhibition of PHDs might induce adverse effects, such as those associated with PHD2 inhibition. Specific disruption of PHD1 induces hypoxic tolerance, without angiogenesis and erythrocytosis, through the reprogramming of basal oxygen metabolism and decreased generation of oxidative stress in hypoxic mitochondria. A specific PHD1 inhibitor might, therefore, offer a novel therapy for abnormal oxygen metabolism not only in the diabetic kidney, but also in other diseases for which hypoxia is a final, common pathway.
慢性缺氧会导致糖尿病患者肾脏中的氧代谢出现一系列异常（例如氧化应激、硝化应激、糖基化终产物形成、羰基应激、内质网应激）。识别这些异常可以帮助我们更好地理解抗高血压药物、控制高血糖和/或高胰岛素血症以及纠正肥胖的治疗益处。机体对抗缺氧的关键是缺氧诱导因子，其活性受脯氨酰羟化酶（PHD）调节，而 PHD 是氧传感器，其抑制可能具有治疗作用。几种动物模型（包括糖尿病肾病模型）已证明小分子 PHD 抑制剂具有肾脏获益，三种不同的 PHD 同工型（PHD1、PHD2 和 PHD3）已被鉴定，其在基因敲除小鼠研究中的作用已被描绘。遗憾的是，目前没有一种抑制剂是针对特定的 PHD 同工型。PHD 的非特异性抑制可能会引起不良反应，如 PHD2 抑制相关的不良反应。通过重新编程基础氧代谢和减少缺氧线粒体中氧化应激的产生，特异性破坏 PHD1 会诱导缺氧耐受，而不会引起血管生成和红细胞增多。因此，特异性 PHD1 抑制剂不仅可为糖尿病肾脏中的异常氧代谢，也可为其他以缺氧为最终共同途径的疾病提供一种新的治疗方法。
