Gain-of-function mutant of angiotensin II receptor, type 1A, causes hypertension and cardiovascular fibrosis in mice

被引:70
作者
Billet, Sandrine
Bardin, Sabine
Verp, Sonia
Baudrie, Veronique
Michaud, Annie
Conchon, Sophie
Muffat-Joly, Martine
Escoubet, Brigitte
Souil, Evelyne
Hamard, Ghislaine
Bernstein, Kenneth E.
Gasc, Jean Marie
Elghozi, Jean-Luc
Corvol, Pierre
Clauser, Eric [1 ]
机构
[1] Univ Paris 05, CNRS, UMR 8104, INSERM Inst Cochin, Paris, France
[2] Univ Descartes, Fac Med, INSERM, U652, Paris, France
[3] INSERM, U36, Coll France, Paris, France
[4] Univ Denis Diderot, INSERM, IFR02, Ctr Explorat Fonctionnelles Integrees, Paris, France
[5] Hop Bichat Claude Bernard, INSERM, U772, Coll France Assistance Publ Hop Paris, Paris, France
[6] Emory Univ, Sch Med, Dept Pathol, Lab Med, Atlanta, GA 30322 USA
关键词
D O I
10.1172/JCI28764
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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 (similar to 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.
引用
收藏
页码:1914 / 1925
页数:12
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