缺氧诱导因子途径对红细胞生成的调控:遗传和药理学扰动的影响。

IF 15.1 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Gregg L Semenza
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引用次数: 12

摘要

红细胞将氧气从肺部输送到身体组织。缺氧刺激肾细胞分泌促红细胞生成素(EPO),从而增加红细胞质量。缺氧诱导因子(hif)介导EPO基因转录激活。HIF-α亚基受到o2依赖的脯氨酰羟基化,然后被von Hippel-Lindau蛋白(VHL)结合,从而触发它们的泛素化和蛋白酶体降解。编码EPO、EPO受体、HIF-2α、脯氨酰羟化酶结构域蛋白2 (PHD2)或VHL的基因突变导致家族性红细胞增生。除O2外,α-酮戊二酸也是PHD2的底物,α-酮戊二酸类似物抑制羟化酶活性。在评估慢性肾脏疾病贫血治疗的III期临床试验中,HIF脯氨酰羟化酶抑制剂在刺激红细胞生成方面与达贝泊汀一样有效。然而,安全性问题主要集中在血栓栓塞上,这也是VHL或HIF-2α突变的一种表型表现,这表明这些事件是HIF脯氨酰羟化酶抑制剂的靶效应。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Regulation of Erythropoiesis by the Hypoxia-Inducible Factor Pathway: Effects of Genetic and Pharmacological Perturbations.

Red blood cells transport O2 from the lungs to body tissues. Hypoxia stimulates kidney cells to secrete erythropoietin (EPO), which increases red cell mass. Hypoxia-inducible factors (HIFs) mediate EPO gene transcriptional activation. HIF-α subunits are subject to O2-dependent prolyl hydroxylation and then bound by the von Hippel-Lindau protein (VHL), which triggers their ubiquitination and proteasomal degradation. Mutations in the genes encoding EPO, EPO receptor, HIF-2α, prolyl hydroxylase domain protein 2 (PHD2), or VHL cause familial erythrocytosis. In addition to O2, α-ketoglutarate is a substrate for PHD2, and analogs of α-ketoglutarate inhibit hydroxylase activity. In phase III clinical trials evaluating the treatment of anemia in chronic kidney disease, HIF prolyl hydroxylase inhibitors were as efficacious as darbepoetin alfa in stimulating erythropoiesis. However, safety concerns have arisen that are focused on thromboembolism, which is also a phenotypic manifestation of VHL or HIF-2α mutation, suggesting that these events are on-target effects of HIF prolyl hydroxylase inhibitors.

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来源期刊
Annual review of medicine
Annual review of medicine 医学-医学:内科
CiteScore
24.90
自引率
0.00%
发文量
58
期刊介绍: The Annual Review of Medicine, which has been published since 1950, focuses on important advancements in diverse areas of medicine. These include AIDS/HIV, cardiology, clinical pharmacology, dermatology, endocrinology/metabolism, gastroenterology, genetics, immunology, infectious disease, neurology, oncology/hematology, pediatrics, psychiatry, pulmonology, reproductive medicine, and surgery. The journal's current volume has transitioned from a gated access model to an open access model through the Annual Reviews' Subscribe to Open program. All articles published in the journal are now available under a CC BY license.
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