A genetic approach for studying the physiology of the type 1A (AT1A) angiotensin receptor.
The ability to create targeted mutations in the mouse genome using homologous recombination in embryonic stem cells (gene targeting) has proved to be an extremely useful experimental approach. Recently, mouse lines have been produced with targeted disruptions of various genes in the renin-angiotensin system, and studies of these animals have provided new insights into a well-studied physiological system. This article will review the phenotype of one of these lines: the Agtr1A (-/-) mouse, which lacks type 1A (AT1A) angiotensin receptors. The AT1A receptor is the major AT1 receptor in mice, and most of the known physiological functions of the renin angiotensin system are mediated by AT1 receptors. Agtr1A (-/-) mice grow and develop normally. In kidneys of Agtr1A (-/-) mice, AT1-specific binding is virtually undetectable and renal AT1-specific binding is reduced by approximately 50% in Agtr1A (+/-) heterozygotes. Agtr1A (-/-) mice have severely blunted vascular responses to angiotensin II and their blood pressures are reduced by more than 20 mm Hg, confirming the important role for this gene locus in mediating vascular responses to angiotensin II and in normal maintenance of blood pressure. Agtr1A (-/-) mice have also been useful in defining angiotensin responses that are mediated by receptors other than AT1A. Studies of mice with RAS gene knockouts represent examples of the productive use of gene targeting as a tool for physiological investigation.
Coffman
T M
TM
Department of Medicine, Duke University Medical Center, Durham, NC, USA.
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D046508:Culture Techniques; D015870:Gene Expression; D007668:Kidney / Q000502:physiology*; D051379:Mice; D008815:Mice, Inbred Strains; D010641:Phenotype; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D012084:Renin-Angiotensin System / Q000235:genetics / Q000502:physiology*
D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; D000804:Angiotensin II