Justin M. Cole

Lack of angiotensin II-facilitated erythropoiesis causes anemia in angiotensin-converting enzyme-deficient mice.

While nephrologists often observe reduced hematocrit associated with inhibitors of angiotensin-converting enzyme (ACE), the basis for this effect is not well understood. We now report that two strains of ACE knockout mice have a normocytic anemia associated with elevated plasma erythropoietin levels. (51)Cr labeling of red cells showed that the knockout mice have a normal total blood volume but a reduced red cell mass. ACE knockout mice, which lack tissue ACE, are anemic despite having normal renal function. These mice have increased plasma levels of the peptide acetyl-SDKP, a possible stem cell suppressor. However, they also show low plasma levels of angiotensin II. Infusion of angiotensin II for 2 weeks increased hematocrit to near normal levels. These data suggest that angiotensin II facilitates erythropoiesis, a conclusion with implications for the management of chronically ill patients on inhibitors of the renin-angiotensin system.

Mice Lacking Endothelial ACE: Normal Blood Pressure With Elevated Angiotensin II

Abstract—Recently, the concept of local renin-angiotensin systems (RAS) capable of generating angiotensin II apart from the circulation has received considerable attention. To investigate this, we generated ACE 1/3 mice in which one allele of ACE is null and the second allele was engineered to express ACE on the surface of hepatocytes. ACE 1/3 mice express no endothelial ACE and lack ACE within the lungs. Their kidneys contain <7.8% the enzyme levels present in control mice. Plasma conversion of angiotensin I to angiotensin II was 43.3% normal. The baseline blood pressure and renal function of the ACE 1/3 mice were normal, probably as a function of a marked increase of both plasma angiotensin I and angiotensin II. When exposed to 2 weeks of a salt-free diet (a stress diet stimulating the RAS), blood pressure in ACE 1/3 mice decreased to 92.3±2.0 mm Hg, a level significantly lower than that of wild-type control mice. The ACE 1/3 mice demonstrate the plasticity of the RAS and show that significant compensation is required to maintain normal, basal blood pressure in a mouse with an impaired local vascular and renal RAS.

Genetic manipulation of the renin-angiotensin system.

The renin-angiotensin system is widely known for its importance in control of blood pressure, electrolyte homeostasis and volume regulation. Recently, renin-angiotensin system function was studied using homologous recombination in embryonic stem cells to manipulate the mouse genome. Angiotensinogen, angiotensin-converting enzyme and angiotensin II receptors were each eliminated in separate lines of mice. These null animals share similar phenotypes, such as a lowering of blood pressure, abnormal renal development, malfunction of the kidney and, unexpectedly, a decrease in hematocrit. In addition, angiotensin-converting enzyme null male mice sire far smaller litters than male wild-type mice. This suggests an unexplored role for angiotensin-converting enzyme in conception. Future studies with these and other genetically engineered mice lines will reveal novel physiological effects of angiotensin II.

Insights derived from ACE knockout mice

The evaluation of ACE knockout mice has illustrated the tremendous physiologic importance of the RAAS. We have discussed how interruption of this system influences blood pressure, renal function, renal development, serum and urine electrolyte composition, haematocrit and male reproductive capacity. This body of data underlines the modelling of the RAAS as a type of biological machine that is positioned to respond to environmental insult and to maintain a homeostasis of blood pressure, blood volume and electrolyte composition. These data also emphasise Harry Goldblatts seminal observation that the kidney and the RAAS are intimately linked in the regulation of normal blood pressure.

Establishing the Role of Angiotensin-Converting Enzyme in Renal Function and Blood Pressure Control through the Analysis of Genetically Modified Mice

Angiotensin II is a vasoconstrictor and a hypertensive peptide that binds to the AT1 receptor and, through both direct and indirect mechanisms, induces salt reabsorption. Also, angiotensin II is thought to be a profibrotic and proproliferative peptide; abundant evidence now suggests that angiotensin

Newer Approaches to Genetic Modeling in Mice : Tissue-Specific Protein Expression as Studied Using Angiotensin-Converting Enzyme (ACE)

Virtually all scientists are aware of the tremendous progress in genetic modeling brought about by targeted homologous recombination in embryonic stem cells. Often called a “knockout mouse”, the ability to modify the mouse genome has created animal models for a large number of disease processes. Typically, targeted genetic modifications are used to inactivate a gene resulting in a mouse null for the corresponding protein. While this approach has been tremendously useful, the most recent work in this area makes use of more subtle genetic modifications to probe the functional role of a protein in an organ-specific or developmental fashion. This review will touch on work from my group and several other laboratories that are using newer approaches to gene targeting with the goal of creating mouse models that ask questions not addressable through the simple inactivation of a gene.