Altered blood pressure responses and normal cardiac phenotype in ACE2-null mice.
The carboxypeptidase ACE2 is a homologue of angiotensin-converting enzyme (ACE). To clarify the physiological roles of ACE2, we generated mice with targeted disruption of the Ace2 gene. ACE2-deficient mice were viable, fertile, and lacked any gross structural abnormalities. We found normal cardiac dimensions and function in ACE2-deficient animals with mixed or inbred genetic backgrounds. On the C57BL/6 background, ACE2 deficiency was associated with a modest increase in blood pressure, whereas the absence of ACE2 had no effect on baseline blood pressures in 129/SvEv mice. After acute Ang II infusion, plasma concentrations of Ang II increased almost 3-fold higher in ACE2-deficient mice than in controls. In a model of Ang II-dependent hypertension, blood pressures were substantially higher in the ACE2-deficient mice than in WT. Severe hypertension in ACE2-deficient mice was associated with exaggerated accumulation of Ang II in the kidney, as determined by MALDI-TOF mass spectrometry. Although the absence of functional ACE2 causes enhanced susceptibility to Ang II-induced hypertension, we found no evidence for a role of ACE2 in the regulation of cardiac structure or function. Our data suggest that ACE2 is a functional component of the renin-angiotensin system, metabolizing Ang II and thereby contributing to regulation of blood pressure.
Gurley
Susan B
SB
Division of Nephrology, Department of Medicine, Duke University and Durham VA Medical Centers, Durham, North Carolina 27705, USA.
Allred
Alicia
A
Le
Thu H
TH
Griffiths
Robert
R
Mao
Lan
L
Philip
Nisha
N
Haystead
Timothy A
TA
Donoghue
Mary
M
Breitbart
Roger E
RE
Acton
Susan L
SL
Rockman
Howard A
HA
Coffman
Thomas M
TM
D000804:Angiotensin II / Q000097:blood / Q000494:pharmacology; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D003433:Crosses, Genetic; D005260:Female; D005298:Fertility; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D007262:Infusions, Intravenous; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D007703:Peptidyl-Dipeptidase A / Q000172:deficiency* / Q000235:genetics*; D012016:Reference Values
D000804:Angiotensin II; D007703:Peptidyl-Dipeptidase A; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2