Evaluation of Anemia in Angiotensin Converting Enzyme (ACE) Knockout Mice.
Using targeted homologous recombination, we made two lines of mice that lack ACE. ACE.1 mice are null for all ACE activity while ACE.2 mice lack tissue ACE but retain 1/3 normal plasma ACE activity. Both strains have a marked decrease in blood pressure and are unable to produce a concentrated urine. ACE.1 mice have renal failure, as measured by a reduced creatinine clearance and an elevated serum creatinine, when compared to wild type mice; ACE.2 mice have no evidence of renal failure as indicated by a normal serum creatinine and creatine clearance. Surprisingly, both ACE.1 and ACE.2 mice are anemic with a reduction in hematocrit (38.5 +/- 1.3% and 38.3 +/- 0.8% respectively vs 48.4 +/- 0.9% for wild type) and serum hemoglobin (12.0 +/- 0.3 mg/dl and 11.7 +/- 0.2 mg/dl vs 14.7 +/- 0.3 mg/dl for wild type). In both strains, serum erythropoietin is elevated. Neither strain differs from wild type in regard to MCV, MCH, or MCHC, nor does either strain show chemical evidence of iron deficiency or hemolysis. Both ACE.1 and ACE.2 mice have equally low serum angiotensin II levels with a significant elevation of serum angiotensin I and the stem cell inhibitory peptide AcSDKP. Due to the presence of renal failure in ACE.1 mice, we have characterized in detail the anemia of ACE.2 mice. These animals demonstrate a significant reduction in total circulating red cell mass (24.2 +/- 1.1 μl/g vs 31.7 +/- 1.8 μl/g for wild type mice) without a change in total blood volume (57.8 +/- 1.2 μl/g vs 56.0 +/- 5.0 μl/g for wild type mice) as measured by the infusion of 51Cr labeled erythrocytes. ACE.2 mice also have an increase in total plasma volume as determined by Evans Blue Dye infusion. The administration of angiotensin II to ACE.2 knockouts significantly increases their hematocrit and serum hemoglobin. Conclusion: The finding of significant anemia in ACE.2 mice, animals without renal failure, suggests a previously unappreciated role of the renin-angiotensin system in regulating erythropoiesis.