ABSTRACT
Angiotensin-converting enzyme (ACE) has been well-recognized for its role in blood pressure regulation. ACE is made by many tissues, though it is most abundantly expressed on the luminal surface of vascular endothelium. ACE knockout mice show a profound phenotype with low blood pressure, but also with hemopoietic and developmental defects, which complicates understanding the biological functions of ACE in individual tissue types. Using a promoter-swapping strategy, several mouse lines with unique ACE tissue expression patterns were studied. These include mice with ACE expression in the liver (ACE 3/3), the heart (ACE 8/8), and macrophages (ACE 10/10). We also investigated mice with a selective inactivation of either the N- or C-terminal ACE catalytic domain. Our studies indicate that ACE plays a role in many other physiologic processes beyond simple blood pressure control.
Subject(s)
Peptidyl-Dipeptidase A/metabolism , Animals , Catalytic Domain , Macrophages/enzymology , Mice , Mice, Knockout , Mutation/genetics , Organ Specificity , Peptidyl-Dipeptidase A/chemistry , Peptidyl-Dipeptidase A/geneticsSubject(s)
Angiotensin II/physiology , Blood Pressure , Peptidyl-Dipeptidase A/physiology , Renin-Angiotensin System/physiology , Animals , Hypertension/etiology , Kidney Diseases/complications , Male , Mice , Mice, Knockout , Myocardium/enzymology , Peptidyl-Dipeptidase A/genetics , Testis/enzymologyABSTRACT
To determine the role of the local renin-angiotensin system in renal function, micropuncture was performed on two lines of mice in which genetic changes to the angiotensin-converting enzyme (ACE) gene markedly reduced or eliminated the expression of renal tissue ACE. Whereas blood pressure is low in one line (ACE 2/2), it is normal in the other (ACE 1/3) due to ectopic hepatic ACE expression. When normalized for renal size, levels of glomerular filtration rate [GFR; microl x min(-1) x g kidney wt(-1) (KW)] and single-nephron GFR (SNGFR; nl x min(-1) x g KW(-1)) were similar between wild-type (WT) and ACE 1/3 mice, while both measures were significantly reduced in ACE 2/2 mice (WT: 500 +/- 63 and 41.7 +/- 3.5; ACE 1/3: 515.8 +/- 71 and 44.3 +/- 3.3; ACE 2/2: 131.4 +/- 23 and 30.3 +/- 3.5). Proximal fractional reabsorption was not significantly different between WT and ACE 1/3 mice (51 +/- 3.5 and 49 +/- 2.3%), and it was increased significantly in ACE 2/2 mice (74 +/- 3.5%). Infusion of ANG II (50 ng x kg(-1) x min(-1)) increased mean arterial pressure by approximately 7 mmHg in all groups of mice and reduced SNGFR in WT and ACE 1/3 mice (to 30.9 +/- 2.8 and 31.9 +/- 2.5 nl x min(-1) x g KW(-1)) while increasing it in ACE 2/2 mice (to 55.3 +/- 5.3 nl x min(-1) x g KW(-1)) despite an increase in total renal vascular resistance. The tubuloglomerular feedback (TGF) response was markedly reduced in ACE 1/3 mice (stop-flow pressure change -2.5 +/- 0.9 mmHg) compared with WT despite similar blood pressures (-8.3 +/- 0.6 mmHg). In ACE 2/2 mice, TGF was absent (-0.7 +/- 0.2 mmHg). We conclude that the chronic lack of ACE, and presumably ANG II generation, in the proximal tubule was not associated with sustained proximal fluid transport defects. However, renal tissue ACE is an important contributor to TGF.
