Inactivation of the gene encoding mouse angiotensin I-converting enzyme (ACE), which converts angiotensin I into angiotensin II, results in anemia in adult animals. This anemia is corrected by angiotensin II, demonstrating the involvement of angiotensin II in adult (definitive) erythropoiesis. We investigated the possible role of the renin-angiotensin system (RAS) in primitive erythropoiesis in the yolk sac of the chicken embryo. Enzymatically active ACE was detected in the yolk sac endoderm, concomitantly with the differentiation of blood islands in the adjacent yolk sac mesoderm. The simultaneous presence of all the other components of the RAS (renin, angiotensinogen, angiotensin II receptor) in the vicinity of the blood islands suggests that this system is involved in erythropoiesis. This role was confirmed by in vivo blockade of the RAS with fosinoprilate, a specific inhibitor of chicken ACE, which decreased hematocrit by 15%. A similar decrease in hematocrit was observed following treatment with the angiotensin II receptor antagonist Sar1-Ile8-Angiotensin II, suggesting that this effect was mediated by angiotensin II. Both treatments affected hematocrit by decreasing erythroblast proliferation. Thus, the RAS, and its effector peptide angiotensin II in particular, modulates primitive erythropoiesis.
IntroductionAngiotensin I converting-enzyme (ACE) is a key element of the renin-angiotensin system (RAS), an integrated system of peptides, enzymes, and membrane receptors, the principal role of which is the regulation of blood pressure and hydromineral homeostasis. This function is accomplished by generation of the octapeptide angiotensin II (Ang II) from the inactive decapeptide angiotensin I (Ang I). 1 Ang II exerts a strong vasopressor effect, but evidence is accumulating that this molecule has several other important functions: it has been found to be proinflammatory, 2 to facilitate the generation of reactive oxygen species (ROS), 3 and to possess hypertrophic and hyperplastic properties in various cell types. [4][5][6][7] The RAS also appears to regulate hematopoiesis, in both experimental models and humans. Indeed, ACE knock-out mice present isolated normochrome anemia, 8 whereas in humans, anemia and leukopenia have been reported following the initiation of treatment with high doses of ACE inhibitors. 9,10 RAS blockade with Ang II receptor antagonists or ACE inhibitors has even been used to treat patients with posttransplantation erythrocytosis or polycythemia vera. 11,12 Finally, further indirect evidence for involvement of the RAS in hematopoiesis is provided by the marked increase in plasma renin concentration reported in patients with chronic obstructive pulmonary disease accompanied by secondary erythrocytosis, 13 suggesting a common causal relationship.This demonstration of a role for ACE in the regulation of adult hematopoiesis led us to investigate the possible role of this enzyme in another important hematopoietic event: primitive hematopoiesis. We used a simple and comprehensive model: the chi...