低氧诱导因子-脯氨酸羟化酶轴在肾性贫血中的作用机制研究进展
曹婧媛, 刘必成^*
东南大学肾脏病研究所/东南大学附属中大医院肾脏科，南京 210009
摘要
肾性贫血是慢性肾脏病患者最常见的并发症之一，主要由促红细胞生成素(erythropoietin, EPO)缺乏和功能性铁缺乏(functional iron deficiency, FID)引起。低氧诱导因子(hypoxia-inducible factor, HIF)是体内参与细胞低氧应答的主要转录因子，而氧依赖性的脯氨酸羟化酶(prolyl hydroxylase, PHD)是HIF降解反应的限速酶，可羟基化HIF的脯氨酸残基，使HIF被蛋白酶体降解，这就是HIF-PHD氧传感途径，亦称HIF-PHD轴。贫血情况下组织缺氧，通过调节HIF-PHD轴可刺激EPO生成、调节铁代谢等，这已成为治疗肾性贫血的新方法。近年来，几种作为选择性HIF-PHD抑制剂的创新药物被成功开发，其中一些药物正在进行临床试验。本文就HIF-PHD轴的概念、调节机制及其在肾性贫血中的作用机制研究进展进行综述。
关键词： 低氧诱导因子; 脯氨酰羟化酶; 低氧诱导因子-脯氨酸羟化酶轴; 肾性贫血
分类号：R339.5;R692.5;R556

Current insights into the role of HIF-PHD axis in renal anemia
CAO Jing-Yuan, LIU Bi-Cheng^*
Institute of Nephrology, Zhongda Hospital, Southeast University, Nanjing 210009, China
Abstract
Renal anemia, mainly caused by the deficiencies of erythropoietin (EPO) and iron metabolism disorder, is one of the most common complications of chronic kidney disease. Hypoxia-inducible factor (HIF) is a class of transcription factors responsible for maintaining homeostasis during oxygen deprivation. In normoxia, HIF is degraded by prolyl hydroxylase (PHD). While under hypoxic conditions, the hydroxylation activity of PHD is inhibited, and the cellular concentration of HIF is elevated, resulting in an increase in endogenous EPO production and iron absorption. Therefore, this regulating pathway, also termed as the HIF-PHD axis, has become a promising therapeutic target of treating renal anemia. Several innovative drugs acting as selective HIF-PHD inhibitors have been successfully developed in the past years, and some of them are undergoing clinical trials. In this review, we will introduce the definition and regulatory mechanism of HIF-PHD axis, as well as current insights into its physiologic and therapeutic role in renal anemia.


Key words: hypoxia inducible factor; prolyl hydroxylase; hypoxia-inducible factor-prolyl hydroxylase axis; renal anemia

收稿日期：2018-01-28　　录用日期：2018-05-07
通讯作者：刘必成　　E-mail: liubc64@163.com
DOI: 10.13294/j.aps.2018.0058
引用本文：
曹婧媛, 刘必成. 低氧诱导因子-脯氨酸羟化酶轴在肾性贫血中的作用机制研究进展[J]. 生理学报 2018; 70 (6): 623-629.
CAO Jing-Yuan, LIU Bi-Cheng. Current insights into the role of HIF-PHD axis in renal anemia. Acta Physiol Sin 2018; 70 (6): 623-629 (in Chinese with English abstract).



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