Murine double nullizygotes of the angiotensin type 1A and 1B receptor genes duplicate severe abnormal phenotypes of angiotensinogen nullizygotes.

Abstract

Rodents are the unique species carrying duplicated angiotensin (Ang) type 1 (AT1) receptor genes, Agtr1a and Agtr1b. After separately generating Agtr1a and Agtr1b null mutant mice by gene targeting, we produced double mutant mice homozygous for both Agtr1a and Agtr1b null mutation (Agtr1a-/-; Agtr1b-/-) by mating the single gene mutants. Agtr1a-/-, Agtr1b-/- mice are characterized by normal in utero survival but decreased ex utero survival rate. After birth they are characterized by low body weight gain, marked hypotension, and abnormal kidney morphology including delayed maturity in glomerular growth, hypoplastic papilla, and renal arterial hypertrophy. These abnormal phenotypes are quantitatively similar to those found in mutant mice homozygous for the angiotensinogen gene (Agt-/-), indicating that major biological functions of endogenous Ang elucidated by the abnormal phenotypes of Agt-/- are mediated by the AT1 receptors. Infusion of Ang II, AT1 blockers, or an AT2 blocker was without effect on blood pressure in Agtr1a-/-; Agtr1b-/- mice, indicating that AT2 receptor does not exert acute depressor effects in these mice lacking AT1 receptors. Also, unlike Agt-/- mice, some Agtr1a-/-; Agtr1b-/- mice have a large ventricular septum defect, suggesting that another receptor such as AT2 is functionally activated in Agtr1a-/-, Agtr1b-/- mice.

Genomic Expression Systems on Hierarchy and Network Leading to Hypertension: Long on History, Short on Facts.

“…3C) exhibited severe hypotension. Although mice deficient for the gene encoding ATla (Agtrla-/-) showed milder hypotension than did those deficient for the gene encoding Agt-/-or Ace-/- (34,35), double nullizygotes without the genes for AT1a and AT1b (Agtrl-/-) were severely hypotensive (36,37) (Fig. 3D).…”

Augmented Renal Vascular nNOS and Renin Protein Expression in Angiotensin Type 1 Receptor Null Mice

“…Targeted null mutations of genes of the major components of the RAS such as angiotensinogen (Agt) (Kim et al 1995), renin (Yanai et al 2000;Chen et al 2007), angiotensin-converting enzyme (ACE) Esther Jr. et al 1996), and AT 1 receptors (Ito et al 1995;Sugaya et al 1995;Matsusaka et al 1996;Oliverio et al 1998a,b;Tsuchida et al 1998) result in reduced blood pressure and abnormal renal vascular and tubular structures. AT 1A 2/2 mice have reduced blood pressure, slight papillary hypoplasia, hyperplasia of renin-producing granular cells (Ito et al 1995;Oliverio et al 1998b;Tsuchida et al 1998), and significantly dilated efferent arterioles (Harrison-Bernard et al 2003,2006.…”

“…AT 1A 2/2 mice have reduced blood pressure, slight papillary hypoplasia, hyperplasia of renin-producing granular cells (Ito et al 1995;Oliverio et al 1998b;Tsuchida et al 1998), and significantly dilated efferent arterioles (Harrison-Bernard et al 2003,2006. AT 1B 2/2 mice show no significant differences in blood pressure, renal architecture (Chen et al 1997;Oliverio et al 1998a), or renal microvascular responses to ANG II (Harrison-Bernard et al 2006) compared with wild-type (WT) mice.…”

Blood pressure and renal hemodynamic effects of angiotensin fragments

“…This notion is supported by data obtained in mice with a double AT 1a (À/À) and AT 1b (À/À), which have a more severe phenotype with a significant lower body weight, kidney weight, blood pressure and heart rate than mice lacking only the AT 1a receptor. 46,52 AT 1 receptors are expressed in many organ systems, including the circulatory system, the central nervous system and the urinary system, and so on, 53 which are presumed to play key functions in blood pressure homeostasis. Interestingly, a cross-transplantation study between genetically matched AT 1 (À/À) and wild-type mice revealed that, for the development of Ang II-induced hypertension and cardiac hypertrophy, renal AT 1 receptors are required.…”