Gain-of-function mutant of angiotensin II receptor, type 1A, causes hypertension and cardiovascular fibrosis in mice.
The role of the renin-angiotensin system has been investigated by overexpression or inactivation of its different genes in animals. However, there is no data concerning the effect of the constitutive activation of any component of the system. A knockin mouse model has been constructed with a gain-of-function mutant of the Ang II receptor, type 1A (AT(1A)), associating a constitutively activating mutation (N111S) with a C-terminal deletion, which impairs receptor internalization and desensitization. In vivo consequences of this mutant receptor expression in homozygous mice recapitulate its in vitro characteristics: the pressor response is more sensitive to Ang II and longer lasting. These mice present with a moderate (~20 mmHg) and stable increase in BP. They also develop early and progressive renal fibrosis and cardiac fibrosis and diastolic dysfunction. However, there was no overt cardiac hypertrophy. The hormonal parameters (low-renin and inappropriately normal aldosterone productions) mimic those of low-renin human hypertension. This new model reveals that a constitutive activation of AT(1A) leads to cardiac and renal fibrosis in spite of a modest effect on BP and will be useful for investigating the role of Ang II in target organs in a model similar to some forms of human hypertension.
Billet
Sandrine
S
Institut Cochin, Université Paris Descartes, CNRS UMR 8104, INSERM U567, Paris, France.
Bardin
Sabine
S
Verp
Sonia
S
Baudrie
Véronique
V
Michaud
Annie
A
Conchon
Sophie
S
Muffat-Joly
Martine
M
Escoubet
Brigitte
B
Souil
Evelyne
E
Hamard
Ghislaine
G
Bernstein
Kenneth E
KE
Gasc
Jean Marie
JM
Elghozi
Jean-Luc
JL
Corvol
Pierre
P
Clauser
Eric
E
D000809:Angiotensins / Q000378:metabolism; D000818:Animals; D001216:Asparagine / Q000235:genetics / Q000378:metabolism; D001794:Blood Pressure; D002318:Cardiovascular Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D018450:Disease Progression; D005260:Female; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D006929:Hyperaldosteronism / Q000150:complications / Q000378:metabolism / Q000473:pathology; D006973:Hypertension / Q000235:genetics / Q000378:metabolism* / Q000401:mortality* / Q000503:physiopathology; D007668:Kidney / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism*; D012083:Renin / Q000097:blood; D015398:Signal Transduction
D000809:Angiotensins; D044140:Receptor, Angiotensin, Type 1; D001216:Asparagine; D012083:Renin