氧平衡对细胞生存至关重要，依赖于其与血红蛋白结合的转运方式。发生缺氧时，促红细胞生成素(EPO)诱导增加，促进红细胞生成和氧气输送。然而，直到1992年Gregg Semenza发现关键的转录因子低氧诱导因子(HIF)时，EPO调控才得到全面的研究(1)。HIF由组成型β亚基和氧依赖性α亚基组成(2)。Peter J.Ratcliffe博士阐明了HIF的氧依赖性调节机制，揭示了HIF-α通过HIF脯氨酸羟化酶(HIF-PH)，对特定脯氨酸残基的氧依赖性羟基化(3-4)。随后William Kaelin Jr.证明了von Hippel-Lindau(VHL)E3连接酶在羟化HIF-α蛋白水解中的重要作用(5)。在缺氧或PHD抑制下，HIF-α易位进入细胞核并与HIF-β形成异源二聚体，从而启动EPO(特定的HIF-2α靶目标)和其他靶目标的转录。在肾功能降低的状态下，肾脏中产生EPO的细胞失去产生EPO的能力，从而导致造血功能降低，血红蛋白下降。Karolinska学院诺贝尔基金会将2019年诺贝尔生理学或医学奖共同颁发给Peter J. Ratcliffe博士、 Gregg L. Semenza 和William G. Kaelin博士，以表彰他们对细胞如何感知和适应氧气变化的重要发现。Peter J. Ratcliffe博士因此成为第一位获得诺贝尔奖得主的肾脏病学家。使用HIF-PH抑制剂的干预措施可作为CKD贫血的一种新型治疗方法(6-7)。

值得注意的是，缺氧和HIF调节涉及许多病理生理过程，包括肾脏疾病。最初由Leon Fine提出的“慢性低氧假说”强调了，肾小管间质区的慢性低氧可能是终末期肾脏疾病的最终常见途径(8)。随后Masaomi Nangaku和Kai-Uwe Eckardt分别对这一概念进行了扩展和验证(9-10)。实验技术的发展使科学家能够监测活体动物细胞内氧气张力，进一步阐明缺氧在肾脏疾病中的关键作用(11)。现在，肾脏的慢性缺氧被认为是治疗的重要靶目标。对于CKD，HIF激活可能是一种有效的治疗方法，不仅是贫血的治疗手段，且还能延缓肾脏疾病的进展。

References

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