Studies of the regulation of erythropoietin (EPO) production by the liver and kidneys, one of the classical physiological responses to hypoxia, led to the discovery of human oxygen-sensing mechanisms, which are now being targeted therapeutically. The oxygen-sensitive signal is generated by 2-oxoglutarate-dependent dioxygenases that deploy molecular oxygen as a co-substrate to catalyse the post-translational hydroxylation of specific prolyl and asparaginyl residues in hypoxia-inducible factor (HIF), a key transcription factor that regulates transcriptional responses to hypoxia. Hydroxylation of HIF at different sites promotes both its degradation and inactivation. Under hypoxic conditions, these processes are suppressed, enabling HIF to escape destruction and form active transcriptional complexes at thousands of loci across the human genome. Accordingly, HIF prolyl hydroxylase inhibitors stabilize HIF and stimulate expression of HIF target genes, including the EPO gene. These molecules activate endogenous EPO gene expression in diseased kidneys and are being developed, or are already in clinical use, for the treatment of renal anaemia. In this Review, we summarize information on the molecular circuitry of hypoxia signalling pathways underlying these new treatments and highlight some of the outstanding questions relevant to their clinical use.

中文翻译：

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低氧信号传导机制：对肾脏病的新影响。

肝脏和肾脏对促红细胞生成素（EPO）产生的调节（对缺氧的经典生理反应之一）的研究导致发现了人类的氧气感应机制，目前该机制已成为治疗的目标。氧敏感信号是由依赖于2-氧戊二酸的双加氧酶产生的，该酶将分子氧作为共底物来催化缺氧诱导因子（HIF）中特定脯氨酰和天冬酰胺基残基的翻译后羟化反应，这是一个关键的转录因子，调节对缺氧的转录反应。HIF在不同位点的羟化作用会促进HIF的降解和失活。在缺氧条件下，这些过程受到抑制，使HIF能够逃脱破坏，并在整个人类基因组的数千个基因座上形成活性转录复合物。因此，HIF脯氨酰羟化酶抑制剂稳定HIF并刺激包括EPO基因在内的HIF靶基因的表达。这些分子激活患病肾脏中的内源性EPO基因表达，并且正在开发或已经在临床上用于治疗肾性贫血。在这篇综述中，我们总结了有关这些新疗法基础上的低氧信号通路分子电路的信息，并重点介绍了与它们的临床使用相关的一些悬而未决的问题。