Sex- and age-related differences in the chronic pressure-natriuresis relationship: role of the angiotensin type 2 receptor

Mirabito, Katrina M; Hilliard, Lucinda M; Kett, Michelle M; Brown, Russell D.; Booth, Sean Carey; Widdop, Robert E; Moritz, Karen M.; Evans, Roger G.; Denton, Kate M.

doi:10.1152/ajprenal.00288.2014

Cited by 54 publications

(60 citation statements)

References 48 publications

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“…In line with previous findings, female mice displayed no significant differences in MAP between 3 and 14 months of age [36, 51]. However, a marked increase in arterial pressure occurred at 18 months of age in the females (~9 mmHg).…”

Section: Discussionsupporting

confidence: 92%

“…The age, 3–5 months (12–20 weeks), is the most common range for studies to be conducted in mice. Moreover, the sex difference in resting arterial pressure, in the order of ~5 mmHg, is consistent with previous reports in mice and other mammalian species, including humans (mice [36], rats [31], rabbits [30], sheep [23], dogs [37], and human [12]). However, not all studies have detected a sex difference in arterial pressure.…”

Section: Discussionsupporting

confidence: 90%

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Sex- and age-related differences in arterial pressure and albuminuria in mice

2016

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BackgroundAnimal models have become valuable experimental tools for understanding the pathophysiology and therapeutic interventions in cardiovascular disease. Yet to date, few studies document the age- and sex-related differences in arterial pressure, circadian rhythm, and renal function in normotensive mice under basal conditions, across the life span. We hypothesized that mice display similar sex- and age-related differences in arterial pressure and renal function to humans.MethodsMean arterial pressure (MAP) and circadian rhythm of arterial pressure were measured over 3 days via radiotelemetry, in 3- and 5-month-old (adult) and 14- and 18-month-old (aged) FVB/N and in 5-month-old (adult) C57BL/6 male and female normotensive mice. In FVB/N mice, albuminuria from 24-h urine samples as well as body, heart, and kidney weights were measured at each age.ResultsTwenty-four-hour MAP was greater in males than females at 3, 5, and 14 months of age. A similar sex difference in arterial pressure was observed in C57BL/6 mice at 5 months of age. In FVB/N mice, 24-h MAP increased with age, with females displaying a greater increase between 3 and 18 months of age than males, such that MAP was no longer different between the sexes at 18 months of age. A circadian pattern was observed in arterial pressure, heart rate, and locomotor activity, with values for each greater during the active (night/dark) than the inactive (day/light) period. The night-day dip in MAP was greater in males and increased with age in both sexes. Albuminuria was greater in males than females, increased with age in both sexes, and rose to a greater level in males than females at 18 months of age.ConclusionsArterial pressure and albuminuria increase in an age- and sex-specific manner in mice, similar to patterns observed in humans. Thus, mice represent a useful model for studying age and sex differences in the regulation of arterial pressure and renal disease. Understanding the mechanisms that underlie the pathophysiology of cardiovascular disease may lead to new and better-tailored therapies for men and women.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 90%

Sex- and age-related differences in arterial pressure and albuminuria in mice

2016

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“…In contrast, females preferentially express the angiotensin type 2 receptor (AT 2 ), which could partially mediate 17␤-estradiol's ability to suppress ANG II-induced hypertension in vivo (1, 2). Aging decreases AT 2 receptor expression in favor of AT 1 receptors in female mice, and in doing so shifts the pressure natriuresis curve to the right, rendering females more susceptible to the effects of ANG II (11,27,28). Further studies are needed in the VCD model of menopause to examine these pathways.…”

Section: Discussionmentioning

confidence: 99%

ANG II-induced hypertension in the VCD mouse model of menopause is prevented by estrogen replacement during perimenopause

Pollow

Romero-Aleshire

Sánchez

et al. 2015

American Journal of Physiology-Regulatory, Integrative and Comp

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Pollow DP, Romero-Aleshire MJ, Sanchez JN, Konhilas JP, Brooks HL. ANG II-induced hypertension in the VCD mouse model of menopause is prevented by estrogen replacement during perimenopause. Am J Physiol Regul Integr Comp Physiol 309: R1546 -R1552, 2015. First published October 21, 2015 doi:10.1152/ajpregu.00170.2015.-Premenopausal females are resistant to the development of hypertension, and this protection is lost after the onset of menopause, resulting in a sharp increase in disease onset and severity. However, it is unknown how a fluctuating ovarian hormone environment during the transition from perimenopause to menopause impacts the onset of hypertension, and whether interventions during perimenopause prevent disease onset after menopause. A gradual transition to menopause was induced by repeated daily injections of 4-vinylcyclohexene diepoxide (VCD). ANG II (800 ng·kg Ϫ1 ·min Ϫ1 ) was infused into perimenopausal and menopausal female mice for 14 days. A separate cohort of mice received 17␤-estradiol replacement during perimenopause. ANG II infusion produced significantly higher mean arterial pressure (MAP) in menopausal vs. cycling females, and 17␤-estradiol replacement prevented this increase. In contrast, MAP was not significantly different when ANG II was infused into perimenopausal and cycling females, suggesting that female resistance to ANG II-induced hypertension is intact during perimenopause. ANG II infusion caused a significant glomerular hypertrophy, and hypertrophy was not impacted by hormonal status. Expression levels of aquaporin-2 (AQP2), a collecting duct protein, have been suggested to reflect blood pressure. AQP2 protein expression was significantly downregulated in the renal cortex of the ANG II-infused menopause group, where blood pressure was increased. AQP2 expression levels were restored to control levels with 17␤-estradiol replacement. This study indicates that the changing hormonal environment in the VCD model of menopause impacts the severity of ANG II-induced hypertension. These data highlight the utility of the ovary-intact VCD model of menopause as a clinically relevant model to investigate the physiological mechanisms of hypertension that occur in women during the transition into menopause.aquaporin-2; glomerular hypertrophy; collecting duct; estrogen PREMENOPAUSAL FEMALES are resistant to the development of hypertension, and this protection is lost after the onset of menopause, resulting in a sharp increase in disease incidence and severity (20). Similarly, resistance to ANG II-induced hypertension has been demonstrated in female rodents. Ovariectomy (the abrupt induction of menopause via the removal of gonads) removes this resistance to ANG II, resulting in a robust ANG II-induced hypertensive response (39). Pharmacological inhibition or genetic ablation of estrogen receptors also increases the hypertensive response to ANG II infusion, suggesting that the loss of 17␤-estradiol signaling during menopause is in part responsible for the shift in blood pressure regulation (40).R...

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“…Potential causes could be a) the model of Ang II induced hypertension, b) the much longer duration of C21 application (7 days versus 3 × 30 minutes), c) the intrarenal route of application, d) the fact that these experiments were performed in female rats, or a combination of some of these parameters. The assumption that female sex is essential is supported by a series of experiments performed by Kate Denton’s group, which showed that adult females express more AT2Rs than males, which leads to lower baseline levels of MAP, but also to a leftward shift of chronic pressure-natriuresis compared to males [12,25]. …”

Section: Effects Of Systemic At2r Stimulation On Blood Pressure Controlmentioning

confidence: 99%

Angiotensin type 2 receptors: blood pressure regulation and end organ damage

Sumners

Kloet

Krause

et al. 2015

Current Opinion in Pharmacology

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In most situations, the angiotensin AT2-receptor (AT2R) mediates physiological actions opposing those mediated by the AT1-receptor (AT1R), including a vasorelaxant effect. Nevertheless, experimental evidence vastly supports that systemic application of AT2R-agonists is blood pressure neutral. However, stimulation of AT2R locally within the brain or the kidney apparently elicits a systemic blood pressure lowering effect. A systemic effect of AT2R stimulation on blood pressure can also be achieved, when the prevailing effect of continuous background AT1R-stimulation is attenuated by low-dose AT1R blockade. Despite a lack of effect on blood pressure, AT2R stimulation still protects from hypertensive end-organ damage. Current data and evidence therefore suggest that AT2R agonists will not be suitable as future anti-hypertensive drugs, but that they may well be useful for end-organ protection in combination with established anti-hypertensives.

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Sex- and age-related differences in the chronic pressure-natriuresis relationship: role of the angiotensin type 2 receptor

Cited by 54 publications

References 48 publications

Sex- and age-related differences in arterial pressure and albuminuria in mice

Sex- and age-related differences in arterial pressure and albuminuria in mice

ANG II-induced hypertension in the VCD mouse model of menopause is prevented by estrogen replacement during perimenopause

Angiotensin type 2 receptors: blood pressure regulation and end organ damage

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