Targeting deletion of angiotensin type 1B receptor gene in the mouse

Abstract

We null mutated the mouse angiotensin type 1B (AT1B) receptor gene (Agtr1b) by gene targeting. To identify the specific cell types carrying high Agtr1b gene transcriptional activities, the AT1B coding exon was replaced with a reporter gene, lacZ. In 6- to 8-wk-old Agtr1b -/- mice, high AT1B transcriptional activity was observed in adrenal zona glomerulosa cells and the testis, including mature and immature spermatic cells, whereas low activity was detected homogeneously in anterior pituitary cells and choroidal plexus vessel walls. A similar pattern was observed in Agtr1b +/- mice with less intensity. Microscopically, the anterior pituitary, heart, adrenal, zona glomerulosa, kidney, and the testis of Agtr1b -/- mice were intact and were indistinguishable from those of Agtr1b +/+ mice. Systemic blood pressure was comparable in Agtr1b -/- and Agtr1b +/+ mice. Moreover, plasma aldosterone level was comparable between the two mouse groups. No compensatory enhancement of AT1A mRNA was found in the kidney and adrenal gland of Agtr1b -/- mice. The observed absence of the abnormal phenotypes in Agtr1b -/- mice, which have been described for homozygous angiotensinogen null mutant mice, indicates that 1) AT1A receptors can take over the role of AT1B receptors in Agtr1b -/- mice or 2) functionally significant non-AT1, non-AT2 receptor(s) may exist for the action of angiotensin.

The angiotensin II type 1 receptor and receptor-associated proteins

“…Mice lacking the expression of these genes show that the AT1A receptor is far more important in the control of blood pressure. Systolic blood pressure is markedly reduced in mice that have no AT1A receptors while no significant difference of blood pressure is observed between wild type control animals and mice lacking the AT1B receptor gene [32][33][34]. Rat AT1A, AT1B and human AT1 5'-flanking region sequences have been determined.…”

Divergent functions of angiotensin II receptor isoforms in the brain

“…Because pharmacological AT 1 receptor antagonists cause equivalent inhibition of both AT 1 isoforms, the relative physiological roles of AT 1A and AT 1B and their relationship to human AT 1 receptor functions have been difficult to identify. Recent gene-targeting experiments have clarified the relative role of the AT 1A and AT 1B receptors in the periphery, demonstrating a predominant role for AT 1A receptors in regulation of vascular tone (10,11). In the brain as in the periphery, expression of AT 1A exceeds that of AT 1B , with the exception of the pituitary gland, where AT 1B expression predominates (12)(13)(14).…”

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

“…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. However, AT 1A 2/2 AT 1B 2/2 mice exhibit marked hypotension, hypoplastic papilla, cortical cysts, renal arterial hypertrophy, renal microvascular disease, and tubulointerstitial injury (Oliverio et al 1998a;Tsuchida et al 1998;Le et al 2004;Ouyang et al 2005).…”