Uniformed Services University of the Health Sciences, Bethesda, MD, United States.
Uniformed Services University of the Health Sciences, Bethesda, MD, United States.
Vitam Horm. 2017;105:57-77. doi: 10.1016/bs.vh.2017.02.001. Epub 2017 Mar 27.
The renin-angiotensin system (RAS) is a key regulator of blood pressure and blood volume homeostasis. The RAS is primarily comprised of the precursor protein angiotensinogen and the two proteases, renin and angiotensin-converting enzyme (ACE). Angiotensin I (Ang I) is derived from angiotensinogen by renin, but appears to have no biological activity. In contrast, angiotensin II (Ang II) that has a variety of biological functions in the cells is converted from Ang I through removal of two-C-terminal residues by ACE. The physiological effects of Ang II are due to Ang II signaling through specific receptor binding, resulting in muscle contraction leading to increased blood pressure and volume. To modulate RAS, three classes of drugs have been developed: (1) renin inhibitors to prevent angiotensinogen conversion to Ang I, (2) ACE inhibitors, to prevent Ang I processing to Ang II and (3) angiotensin receptor blockers, to inhibit Ang II signaling through its receptor. Studies using the RAS inhibitors and Ang II demonstrated that RAS signaling mediates actions of Ang II in the regulation of proliferation and differentiation of specific hematopoietic cell types, especially in the red blood cell lineage. Accumulating evidence indicates that RAS regulates EPO, an essential mediator of red cell production, for human anemia and erythropoiesis in vivo and in vitro. The regulation of EPO expression by Ang II may be responsible for maintaining red blood cell homeostasis. This review highlights the biological roles of RAS for blood cell and EPO homeostasis through Ang II signaling. The molecular mechanism for Ang II-induced EPO production of the cell or tissue type-specific expression is discussed.
肾素-血管紧张素系统（RAS）是血压和血容量稳态的主要调节因子。RAS 主要由前体蛋白血管紧张素原和两种蛋白酶，肾素和血管紧张素转换酶（ACE）组成。血管紧张素 I（Ang I）由肾素从血管紧张素原衍生而来，但似乎没有生物学活性。相比之下，血管紧张素 II（Ang II）通过 ACE 去除两个 C 末端残基从 Ang I 转化而来，具有多种细胞内生物学功能。Ang II 的生理作用归因于 Ang II 通过与特定受体结合进行信号转导，导致肌肉收缩，从而导致血压和容量增加。为了调节 RAS，已经开发了三类药物：（1）肾素抑制剂，以防止血管紧张素原转化为 Ang I；（2）ACE 抑制剂，以防止 Ang I 转化为 Ang II；（3）血管紧张素受体阻滞剂，以抑制 Ang II 通过其受体进行信号转导。使用 RAS 抑制剂和 Ang II 的研究表明，RAS 信号转导介导 Ang II 在调节特定造血细胞类型的增殖和分化中的作用，尤其是在红细胞谱系中。越来越多的证据表明，RAS 调节 EPO，即红细胞生成的必需介质，用于体内和体外的人类贫血和红细胞生成。Ang II 对 EPO 表达的调节可能是维持红细胞内稳态的原因。本综述通过 Ang II 信号转导强调了 RAS 对血细胞和 EPO 内稳态的生物学作用。讨论了细胞或组织类型特异性表达的 Ang II 诱导 EPO 产生的分子机制。
