Differential ANG II generation in plasma and tissue of mice with decreased expression of the ACE gene

Abstract

We utilized mice with homozygous disruption of angiotensin-converting enzyme (ACE) (-/-), mice with heterozygous deletion of ACE (+/-), and wild-type mice (+/+) to test the hypothesis that genetic variation in ACE modulates tissue and plasma angiotensin (ANG) II concentrations. With the use of ANG I as substrate, kidney, heart, and lung ACE activity was reduced 80% in -/- mice compared with +/+ mice. However, ANG II concentrations and ANG II-to-ANG I ratios in the kidney, heart, and lung did not differ among genotypes. In contrast, plasma ANG II concentrations in -/- mice were <2 fmol/ml, whereas plasma ANG I concentrations were extremely high (765 fmol/ml). Chymase activity was increased 14-fold in the kidney (P < 0.05) and 1.5-fold in the heart (P < 0.05) of -/- versus +/+ mice but did not differ among genotypes in the lung. ANG II formation from enzymes other than ACE and chymase contributed <2% of total ANG II formation in all genotypes. These data suggest that ACE is essential to ANG II formation in the vascular space, whereas chymase may provide an important mechanism in maintaining steady-state ANG II levels in tissue.

Major role for ACE-independent intrarenal ANG II formation in type II diabetes

“…However, Campbell et al (4) demonstrated a significant suppression of ANG II in the kidney of mice with reduced somatic ACE gene expression. The data of Wei et al (43) in the ACE null mice are consistent with our findings of reduced ACE activity, yet similar ANG I and ANG II peptide levels in the diabetic kidney, and suggest that intrarenal ACEindependent pathways for ANG II formation may predominate in the diabetic kidney.…”

A Thrombospondin-1 Antagonist of Transforming Growth Factor-β Activation Blocks Cardiomyopathy in Rats with Diabetes and Elevated Angiotensin II

“…44,45 Radioimmunoassay of relevant peaks revealed detectable levels of angiotensin (Ang) II in all left ventricular (LV) samples examined. Antibodies to Ang II were raised in New Zealand White rabbits immunized against peptide conjugated to poly-L-lysine, as previously described.…”

Effect of Reduced Angiotensin-Converting Enzyme Gene Expression and Angiotensin-Converting Enzyme Inhibition on Angiotensin and Bradykinin Peptide Levels in Mice

“…These authors also reported that chymase levels were increased 14-fold in kidney and 1.5-fold in heart of ACE KO mice, in comparison with WT mice, and they suggested that prolonged suppression of ACE activity may lead to the induction of alternate enzymatic pathways of angiotensin II formation in tissue. 2 We and others have shown that ACE inhibition produces marked reduction in angiotensin II levels in blood and tissues of rats and humans. [3][4][5][6] However, ACE inhibition is reported to have variable effects on angiotensin II levels in mice.…”

“…Many patients receiving ACE inhibitor therapy fail to show reduction in angiotensin II levels, leading to the proposal that alternate enzymes such as chymase may convert angiotensin I to angiotensin II. 1 In support of this proposal, Wei et al 2 reported that although plasma angiotensin II levels of ACE gene knockout (KO) mice were reduced to below the limit of detection, angiotensin II levels in kidney, heart, and lung of ACE KO mice were no different from the levels in wild-type (WT) mice. These authors also reported that chymase levels were increased 14-fold in kidney and 1.5-fold in heart of ACE KO mice, in comparison with WT mice, and they suggested that prolonged suppression of ACE activity may lead to the induction of alternate enzymatic pathways of angiotensin II formation in tissue.…”