Department of Cell physiology and Metabolism, University of Geneva, Geneva, Switzerland.
Institute of Physiology, University of Zurich, Zurich, Switzerland.
Nephrol Dial Transplant. 2021 Sep 27;36(10):1782-1790. doi: 10.1093/ndt/gfaa091.
Chronic kidney disease (CKD) is defined as an alteration of kidney structure and/or function lasting for >3 months [1]. CKD affects 10% of the general adult population and is responsible for large healthcare costs [2]. Since the end of the last century, the role of hypoxia in CKD progression has controversially been discussed. To date, there is evidence of the presence of hypoxia in late-stage renal disease, but we lack time-course evidence, stage correlation and also spatial co-localization with fibrotic lesions to ensure its causative role. The classical view of hypoxia in CKD progression is that it is caused by peritubular capillary alterations, renal anaemia and increased oxygen consumption regardless of the primary injury. In this classical view, hypoxia is assumed to further induce pro-fibrotic and pro-inflammatory responses, as well as oxidative stress, leading to CKD worsening as part of a vicious circle. However, recent investigations tend to question this paradigm, and both the presence of hypoxia and its role in CKD progression are still not clearly demonstrated. Hypoxia-inducible factor (HIF) is the main transcriptional regulator of the hypoxia response. Genetic HIF modulation leads to variable effects on CKD progression in different murine models. In contrast, pharmacological modulation of the HIF pathway [i.e. by HIF hydroxylase inhibitors (HIs)] appears to be generally protective against fibrosis progression experimentally. We here review the existing literature on the role of hypoxia, the HIF pathway and HIF HIs in CKD progression and summarize the evidence that supports or rejects the hypoxia hypothesis, respectively.
慢性肾脏病（CKD）定义为肾脏结构和/或功能改变持续>3 个月[1]。CKD 影响 10%的普通成年人群，导致大量医疗保健费用[2]。自上世纪末以来，缺氧在 CKD 进展中的作用一直存在争议。迄今为止，虽然有证据表明晚期肾脏疾病存在缺氧，但我们缺乏时程证据、分期相关性以及与纤维化病变的空间共存，无法确保其因果关系。CKD 进展中缺氧的经典观点认为，缺氧是由肾小管周围毛细血管改变、肾性贫血和耗氧量增加引起的，而与原发性损伤无关。在这种经典观点中，缺氧被认为会进一步诱导促纤维化和促炎反应以及氧化应激，导致 CKD 恶化，形成恶性循环。然而，最近的研究倾向于质疑这一观点，缺氧的存在及其在 CKD 进展中的作用仍未得到明确证实。缺氧诱导因子（HIF）是缺氧反应的主要转录调节因子。遗传 HIF 调节在不同的小鼠模型中对 CKD 进展的影响不同。相比之下，HIF 通路的药理学调节（即通过 HIF 羟化酶抑制剂（HIs））在实验中似乎普遍对纤维化进展具有保护作用。我们在这里回顾了关于缺氧、HIF 通路和 HIF HIs 在 CKD 进展中的作用的现有文献，并总结了分别支持或否定缺氧假说的证据。
