Constitutively active receptor of angiotensin induces hypertension and cardiovascular fibrosis in mouse
A major player in regulating blood pressure is the renin angiotensin system. Its effector is angiotensin II, which is a potent vasoconstrictor and regulates hydro-electrolytic balance, both resulting in hypertension. Therefore, several routinely used treatments of hypertension inhibit the production or the action of angiotensin.
But, is angiotensin II per se able to determine cardiac and vascular alterations leading to the complications describe above, independently of hypertension ? The benefic effects of angiotensin blockers in non-hypertensive patients presenting cardiovascular diseases and in vivo studies using cell models sustain together this hypothesis.
A team of the Cochin Institute (U567 Inserm/ UMR8104 CNRS/Université Paris Descartes) has recently demonstrated in a direct manner and in vivo that angiotensin II has a deleterious effect on cardiovascular system. They have replaced the wild type mAgtr1a gene of the mouse genome with an homologous mutated one coding a receptor, which is activated permanently and independently of angiotensin. These mice develop a early and progressive cardiovascular fibrosis.
Present treatments of hypertension and the numerous animal models inactivating or overexpressing the genes of the renin angiotensin system (RAS) demonstrate together the importance of this endocrine system in the regulation of blood pressure. However, genetic studies in human were unable to identify monogenic forms of familial hypertension linked to these genes and even more no linkage or association of the disease with polymorphisms of these genes. At this stage there was no experimental evidence that quantitative or qualitative genetic alterations of the RAS proteins may have deleterious consequences, such as hypertension or cardiovascular diseases.
Angiotensin II receptors are G protein coupled receptors (GPCR). Several receptors of this family exhibit natural activating mutations responsible for diseases due to the excessive and unregulated production of second messengers. Such mutations were not identified for the angiotensin receptor, neither in hypertension nor in candidate diseases such as Conn adenoma. We have identified several activating mutations of the angiotensin receptor using random mutagenesis (Parnot C. et al. PNAS, 2000, 97:6715) and one of them was introduced in the mouse genome in order to answer the following questions:
- Is such a mutation able to produce hypertension and what will be its phenotype?
- What are the consequences of an isolated activation of the angiotensin receptor on the target tissues?
- Is such a constitutively activated receptor oncogenic?
In the mouse genome, we have replaced by homologous recombination the mAgtr1a gene by a homologous one bearing 2 mutations: a constitutively activating mutation (N111S) and a C-terminal deletion, which impairs the constitutive internalization and desensitization of such a receptor.
Homozygous mice for these mutations are viable and fertile. They present an elevated blood pressure (20mm Hg) with low renin and angiotensin plasma levels. This phenotype is similar to a very frequent form of human hypertension.
Quantitatively normal expression of this activated receptor in target tissues is not oncogenic but determines a early, deleterious and progressive fibrosis in the heart, blood vessels and kidneys. This fibrosis appears to be independent of hypertension. Conversely, a late cardiovascular hypertrophy is only observed in the most hypertensive animals.
This new animal model of hypertension due to expression of a spontaneously active angiotensin receptor opens new and interesting fields to understand the role of this hormone in the development of cardiovascular diseases and especially in the initiation and development of atherosclerosis. These coming studies would reinforce the idea that treatments blocking the production or action of angiotensin are efficient in cardiovascular diseases, independently of their action on blood pressure.
Reference:
Billet, S ; Bardin S, Verp S, Baudrie V, Michaud A, Conchon S, Muffat-Joly M, Escoubet B, Souil E, Hamard G, Bernstein KE, Gasc JM, Elghozi JL, Corvol P & Clauser E. Gain-of-function of angiotensin II AT1A receptor causes hypertension and cardiovascular fibrosis in mice.
J Clin Invest,2007, 117: 1914-25.
Contact
Eric CLAUSER
Institut Cochin
Tel: 33 1 53 73 27 50
Email : clauser@cochin.inserm.fr
