Phenotypes associated with this allele

• Allele Symbol: Agtr2^tm1Gsb
• Allele Name: targeted mutation 1, Gregory S Barsh
• Allele ID: MGI:1857123
• Summary: 5 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Agtr2^tm1Gsb/Agtr2^tm1Gsb	involves: 129S1/Sv * 129X1/SvJ	MGI:3805913
cx2	Agtr1a^tm1Afu/Agtr1a^tm1Afu Agtr2^tm1Gsb/Y	mixed	MGI:3639148
ot3	Agtr2^tm1Gsb/Y	FVB.129-Agtr2^tm1Gsb	MGI:3639106
ot4	Agtr2^tm1Gsb/Y	involves: 129S1/Sv * 129X1/SvJ	MGI:6402560
ot5	Agtr2^tm1Gsb/Y	involves: 129S1/Sv * 129X1/SvJ * FVB/N	MGI:2655624

Genotype
MGI:3805913

hm1

• Allelic Composition: Agtr2^tm1Gsb/Agtr2^tm1Gsb
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

homeostasis/metabolism

increased susceptibility to injury ( J:100334 )

• mice exposed to acid aspiration to induce acute lung injury show aggravated acute lung injury

Genotype
MGI:3639148

cx2

• Allelic Composition: Agtr1a^tm1Afu/Agtr1a^tm1Afu; Agtr2^tm1Gsb/Y
• Genetic Background: mixed

behavior/neurological

increased fluid intake ( J:107851 )

♂ • i.c.v injection of angiotensin II (100 ng) increases water intake 5-fold in adult wild-type males but has no significant effect on water intake in males homozygous for Agtr1a^tm1Afu and hemizygous for Agtr2^tm1Gsb

cardiovascular system

abnormal systemic arterial blood pressure ( J:107851 )

♂ • adult males homozygous for Agtr1a^tm1Afu and hemizygous for Agtr2^tm1Gsb show no apparent physiological changes (e.g. body weight gain) or histological abnormalities in the heart, artery or brain

♂ • however, these mice display a higher increase in SBP after central injection of a high dose of angiotensin II (200 ng) relative to Agtr1a^tm1Afu homozygotes

Genotype
MGI:3639106

ot3

• Allelic Composition: Agtr2^tm1Gsb/Y
• Genetic Background: FVB.129-Agtr2^tm1Gsb

mortality/aging

increased susceptibility to induced morbidity/mortality ( J:103066 )

♂ • on day 14 after myocardial infarction (MI), male hemizygotes exhibit a significanlty higher mortality rate (62.9%) relative to wild-type males (39.7%)

cardiovascular system

abnormal vasculogenesis ( J:103237 )

♂ • in male hemizygotes, VSMC-specific contractile proteins increase from birth to 8 weeks of age to a lesser extent relative to wild-type mice, suggesting impaired vascular development

abnormal vascular smooth muscle morphology ( J:103237 )

♂ • hemizygous males exhibit delayed expression of late VSMC differentiation markers, as shown by significantly reduced protein levels of calponin and caldesmon in mutant thoracic aorta at 2 and 4 weeks after birth

♂ • in contrast, no differences in alpha-smooth muscle actin expression (an early VSMC differentiation marker) are noted at E20, P1 or thereafter

vascular smooth muscle hypertrophy ( J:103376 )

♂ • at 10-12 months, mutant arteries show a significant increase in media thickness and SMC size, as shown by an ~82%, ~21% and ~26% increase of media myocyte size in femoral resistance arteries, aortas, and renal resistance arteries, respectively

♂ • no alterations in intima, adventitia, or internal and external elastic membranes are observed

♂ • in association with VSMC hypertrophy, mutant aortic lysates exhibit a 65% increase in P70S6 kinase phosphorylation levels relative to wild-type aortas

♂ • treatment with an ACE inhibitor (captopril) for 8 weeks abolishes the increased pressure responsiveness, vascular hypertrophy, and enhanced P70S6 kinase phosphorylation in mutant mice

dilated heart left ventricle ( J:103066 )

♂ • after MI, male hemizygotes exhibit significantly increased LV/body weight ratios (on day 14) and LV end-diastolic and end-systolic dimensions (on day 7) relative to wild-type mice, as a result of elongated myocyte length and/or increased interstitial weight

abnormal response to cardiac infarction ( J:103066 )

♂ • after MI, male hemizygotes exhibit enhanced LV dilation on days 3 and 7 as well as increased mortality in the first 2 weeks due to heart failure

♂ • however, no differences in the rates of ventricular arrhythmia, cardiac rupture or blood pressures are observed between mutant and wild-type males after MI

♂ • notably, interstitial fibrosis develops in the 4th week after MI and is significantly larger in mutant mice than in wild-type mice (not shown)

abnormal systemic arterial blood pressure ( J:103237 )

♂ • at 4 weeks, hemizygous males exhibit a significantly higher basal mean blood pressure relative to wild-type mice (105.2 4.5 vs 87.53.9 mmHg, respectively); however, no differences in blood pressure are noted at 8 weeks of age (109.2 5.7 versus 107.7 4.8 mmHg)

abnormal vasoconstriction ( J:103237 )

♂ • at 4 weeks, hemizygous males exhibit a significantly higher mean blood pressure than wild-type mice, when caldesmon and calponin contents are reduced in mutant mice; along with the increase in caldesmon and calponin in mutant aorta, the blood pressure difference disappears at age 8 weeks, suggesting a role in modulating smooth muscle contractility

increased vasoconstriction ( J:103376 )

♂ • at 10-12 months, male hemizygotes show no significant differences in arterial blood pressure, circulating RAS activity, heart rate, maximal LV systolic pressure or maximal LV contractility (dP/dtmax) and LV ejection fractions relative to wild-type males

♂ • however, isolated femoral arteries from male hemizygotes display enhanced vasoconstriction to angiotensin II, norepinephrine, and K⁺ depolarization relative to wild-type males

♂ • no differences in acetylcholine-induced vasorelaxation are observed, indicating unaltered endothelial function

muscle

abnormal vascular smooth muscle morphology ( J:103237 )

♂ • hemizygous males exhibit delayed expression of late VSMC differentiation markers, as shown by significantly reduced protein levels of calponin and caldesmon in mutant thoracic aorta at 2 and 4 weeks after birth

♂ • in contrast, no differences in alpha-smooth muscle actin expression (an early VSMC differentiation marker) are noted at E20, P1 or thereafter

vascular smooth muscle hypertrophy ( J:103376 )

♂ • at 10-12 months, mutant arteries show a significant increase in media thickness and SMC size, as shown by an ~82%, ~21% and ~26% increase of media myocyte size in femoral resistance arteries, aortas, and renal resistance arteries, respectively

♂ • no alterations in intima, adventitia, or internal and external elastic membranes are observed

♂ • in association with VSMC hypertrophy, mutant aortic lysates exhibit a 65% increase in P70S6 kinase phosphorylation levels relative to wild-type aortas

♂ • treatment with an ACE inhibitor (captopril) for 8 weeks abolishes the increased pressure responsiveness, vascular hypertrophy, and enhanced P70S6 kinase phosphorylation in mutant mice

abnormal vasoconstriction ( J:103237 )

♂ • at 4 weeks, hemizygous males exhibit a significantly higher mean blood pressure than wild-type mice, when caldesmon and calponin contents are reduced in mutant mice; along with the increase in caldesmon and calponin in mutant aorta, the blood pressure difference disappears at age 8 weeks, suggesting a role in modulating smooth muscle contractility

increased vasoconstriction ( J:103376 )

♂ • at 10-12 months, male hemizygotes show no significant differences in arterial blood pressure, circulating RAS activity, heart rate, maximal LV systolic pressure or maximal LV contractility (dP/dtmax) and LV ejection fractions relative to wild-type males

♂ • however, isolated femoral arteries from male hemizygotes display enhanced vasoconstriction to angiotensin II, norepinephrine, and K⁺ depolarization relative to wild-type males

♂ • no differences in acetylcholine-induced vasorelaxation are observed, indicating unaltered endothelial function

homeostasis/metabolism

abnormal response to cardiac infarction ( J:103066 )

♂ • after MI, male hemizygotes exhibit enhanced LV dilation on days 3 and 7 as well as increased mortality in the first 2 weeks due to heart failure

♂ • however, no differences in the rates of ventricular arrhythmia, cardiac rupture or blood pressures are observed between mutant and wild-type males after MI

♂ • notably, interstitial fibrosis develops in the 4th week after MI and is significantly larger in mutant mice than in wild-type mice (not shown)

Genotype
MGI:6402560

ot4

• Allelic Composition: Agtr2^tm1Gsb/Y
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ

homeostasis/metabolism

increased susceptibility to injury ( J:100334 )

♂ • mice exposed to acid aspiration to induce acute lung injury show aggravated acute lung injury

Genotype
MGI:2655624

ot5

• Allelic Composition: Agtr2^tm1Gsb/Y
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * FVB/N

behavior/neurological

abnormal fluid intake ( J:29456 )

♂ • hemizygous males develop normally and show no significant differences in daily water intake relative to wild-type males when water is freely accessible

♂ • however, after 40 hrs of water deprivation, hemizygous males exhibit an impaired drinking response relative to wild-type males

♂ • in addition, water-deprived hemizygous males display a significantly reduced body weight restoration relative to wild-type males at 3 hrs after water repletion

increased fluid intake ( J:107851 )

♂ • i.c.v injection of angiotensin II (100 ng) increases water intake 5-fold in adult wild-type males; this increase is reduced by ~40% in male hemizygotes relative to wild-type males

♂ • in wild-type males, the effect of angiotensin II on water intake is significantly inhibited by valsartan and by PD-123319; in male hemizygotes this effect is significantly inhibited by valsartan, but not PD-123319

decreased locomotor activity ( J:29456 )

♂ • in a photobeam activity cage, hemizygous males exhibit significantly reduced locomotor activity during the dark period of the day/night cycle, particularly during the first 6 hrs (day 1); a smaller effect is noted during the dark period of the cycle on the second test day

♂ • in contrast, no significant differences are observed during the light period of the light/dark cycle

cardiovascular system

abnormal systemic arterial blood pressure ( J:29456 )

♂ • hemizygous males display no differences in baseline aortic blood pressure and heart rate relative to wild-type males

♂ • however, hemizygous males display increased vasopressor responsiveness to low-dose exogenous angiotensin II after endogenous angiotensin II production has been inhibited by captopril

increased systemic arterial systolic blood pressure ( J:107851 )

♂ • adult hemizygous males show no significant differences in basal SBP relative to adult wild-type males (101.9 0.9 vs 98.4 0.8 mmHg, respectively)

♂ • however, after central injection of angiotensin II, hemizygous males exhibit a significantly larger increase in SBP within the range of 50-200 ng, with no notable differences in the time course of the pressor response

♂ • in hemizygous males, the pressor response after central injection of angiotensin II (100 ng) is inhibited ~45% by valsartan but this inhibition is significantly smaller than that in wild-type males; PD-123319 has no significant effect on SBP in mutant males