Abstract

The renin–angiotensin system (RAS) plays a central role in blood pressure regulation. Although clinical and experimental studies have suggested that inhibition of RAS is associated with progression of anemia, little evidence is available to support this claim. Here we report that knockout mice that lack angiotensin II, including angiotensinogen and renin knockout mice, exhibit anemia. The anemia of angiotensinogen knockout mice was rescued by angiotensin II infusion, and rescue was completely blocked by simultaneous administration of AT1 receptor blocker. To genetically determine the responsible receptor subtype, we examined AT1a, AT1b, and AT2 knockout mice, but did not observe anemia in any of them. To investigate whether pharmacological AT1 receptor inhibition recapitulates the anemic phenotype, we administered AT1 receptor antagonist in hypotensive AT1a receptor knockout mice to inhibit the remaining AT1b receptor. In these animals, hematocrit levels barely decreased, but blood pressure further decreased to the level observed in angiotensinogen knockout mice. We then generated AT1a and AT1b double-knockout mice to completely ablate the AT1 receptors; the mice finally exhibited the anemic phenotype. These results provide clear evidence that although erythropoiesis and blood pressure are negatively controlled through the AT1 receptor inhibition in vivo, the pathways involved are complex and distinct, because erythropoiesis is more resistant to AT1 receptor inhibition than blood pressure control.

Highlights

  • The renin–angiotensin system (RAS) plays an important role in blood pressure regulation and fluid homeostasis in the circulatory system

  • Considering the almost identical degree of severity of anemia in Agt (-/-), Ren(-/-) and angiotensin converting enzyme (ACE) knockout mice, we speculate that the anemic phenotype observed in these animals is attributable to complete loss of Angiotensin II (Ang II) production, rather than the accumulation of substrates of or the loss of products of ACE or renin enzymes, because Ang II and its fragments, such as Ang (1–7) or Ang III, are the only common peptides produced from angiotensinogen, renin, and ACE

  • No significant differences in the mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC) were found between the groups, indicating that Agt(-/-) and Ren(-/-) are normocytic and normochromic anemia (Table 1)

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Summary

Introduction

The renin–angiotensin system (RAS) plays an important role in blood pressure regulation and fluid homeostasis in the circulatory system. It exerts various actions in diverse target tissues. Diverse actions of Ang II are mediated by several Ang II receptor subtypes present in a variety of target tissues. Two Ang II receptor subtypes, designated as Ang II type 1 (AT1) and Ang II type 2 (AT2), have been identified in humans. Two AT1 receptor isoforms, AT1a and AT1b, have been identified, and blood pressure regulation is mediated mainly through the AT1a receptor, which is expressed at higher levels than the AT1b receptor in most organs [1]. No apparent phenotype has been identified in AT1b receptor knockout mice (AT1b(-/-)) [2]

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