Estrogen upregulates renal angiotensin II AT1 and AT2 receptors in the rat

Baiardi, Gustavo; Macova, Miroslava; Armando, Inés; Ando, Hiromichi; Tyurmin, Dmitri; Saavedra, Juan M.

doi:10.1016/j.regpep.2004.06.021

Cited by 107 publications

(84 citation statements)

References 43 publications

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Section: Discussionmentioning

confidence: 98%

“…Previous studies that have measured the renal expression of angiotensin receptors in rodents have identified AT 2 R expression in the glomeruli, afferent arteriole, arcuate arteries and veins, and medullary descending vasa recta, 10,36,37 with evidence of greater renal AT 2 R expression in the female renal vasculature. 37 We and others previously have reported greater expression of the AT 2 R in the kidney of female vs male rats 5,37 and mice. 10 Given this evidence that the AT 2 R is upregulated in females and protects females against Ang II-induced vasoconstriction, the reduction in RBF and GFR at low RPP during AT 2 R blockade that we observed in females could be the consequence of a number of mechanisms.…”

Section: Discussionmentioning

confidence: 98%

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Gender Differences in Pressure-Natriuresis and Renal Autoregulation

et al. 2011

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Abstract-Sexual dimorphism in arterial pressure regulation has been observed in humans and animal models. The mechanisms underlying this gender difference are not fully known. Previous studies in rats have shown that females excrete more salt than males at a similar arterial pressure. The renin-angiotensin system is a powerful regulator of arterial pressure and body fluid volume. This study examined the role of the angiotensin type 2 receptor (AT 2 R) in pressure-natriuresis in male and female rats because AT 2 R expression has been reported to be enhanced in females.Renal function was examined at renal perfusion pressures of 120, 100, and 80 mm Hg in vehicle-treated and AT 2 R antagonist-treated (PD123319; 1 mg/kg/h) groups. The pressure-natriuresis relationship was gender-dependent such that it was shifted upward in female vs male rats (PϽ0.001). AT 2 R blockade modulated the pressure-natriuresis relationship, shifting the curve downward in male (PϽ0.01) and female (PϽ0.01) rats to a similar extent. In females, AT 2 R blockade also reduced the lower end of the autoregulatory range of renal blood flow (PϽ0.05) and glomerular filtration rate (PϽ0.01). Subsequently, the renal blood flow response to graded angiotensin II infusion was also measured with and without AT 2 R blockade. We found that AT 2 R blockade enhanced the renal vasoconstrictor response to angiotensin II in females but not in males (PϽ0.05). In conclusion, the AT 2 R modulates pressure-natriuresis, allowing the same level of sodium to be excreted at a lower pressure in both genders. However, a gender-specific role for the AT 2 R in renal autoregulation was evident in females, which may be a direct vascular AT 2 R effect. (Hypertension. 2011;57:275-282.)Key Words: angiotensin type 2 receptor Ⅲ gender differences Ⅲ hypertension Ⅲ natriuresis Ⅲ renal blood flow Ⅲ sodium I t is well-established that women are protected from cardiovascular and renal disease relative to men before menopause. 1 However, the mechanisms responsible for this gender difference are poorly understood, partly because females remain underrepresented in human clinical trials and animal studies. 2,3 Evidence suggests that estrogen plays a protective role against cardiovascular disease in women, 4 and previous studies have identified gender differences in the activity of the renin-angiotensin system (RAS), 1 a major regulator of arterial pressure.Studies in rodents have also revealed major gender differences in the expression of RAS components and differences in the way males and females respond to stimulation and inhibition of the RAS under physiological and pathophysiological circumstances. [5][6][7][8] Recently, with the discovery of angiotensin-converting enzyme 2, a depressor axis to the RAS has been identified 9 that incorporates the angiotensin type 2 receptor (AT 2 R), which is upregulated by estrogen. 7,10 Previously, we have demonstrated that the vasodepressor RAS pathways are enhanced in females and that the AT 2 R has a depressor influence on the response to chronic ang...

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 98%

Gender Differences in Pressure-Natriuresis and Renal Autoregulation

et al. 2011

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“…Studies examining angiotensin receptor expression in rodents have reported AT 2 R expression in the glomeruli, afferent arterioles, arcuate arteries, and medullary descending vasa recta, 12,18,19 with evidence of greater AT 2 R expression in the female vasculature. 18 The sex-specific response to AT 2 R stimulation is also consistent with our findings reported recently in normotensive rats that the AT 2 R plays a more significant role in the female versus male renal vasculature. 13 In response to exogenous administration of Ang II, we previously observed dose-dependent decreases in RBF in both males and females.…”

Section: Discussionmentioning

confidence: 99%

Sex-Specific Influence of Angiotensin Type 2 Receptor Stimulation on Renal Function

et al. 2012

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Abstract-The renin-angiotensin system is a powerful regulator of arterial pressure and body fluid volume. Increasing evidence suggests that the angiotensin type 2 receptor (AT 2 R), which mediates the vasodilatory and natriuretic actions of angiotensin peptides, is enhanced in females and may, therefore, represent an innovative therapeutic target. We investigated the therapeutic potential of direct AT 2 R stimulation on renal function in 11-to 12-week-old anesthetized male and female Sprague-Dawley rats. Renal blood flow was examined in response to a graded infusion of the highly selective, nonpeptide AT 2 R agonist, compound 21 (100, 200, and 300 ng/kg per minute), in the presence and absence of AT 2 R blockade (PD123319; 1 mg/kg per hour). Direct AT 2 R stimulation significantly increased renal blood flow in both males and females, without influencing arterial pressure. This was dose dependent in females only and occurred to a greater extent in females at the highest dose of compound 21 administered (males: 13.1Ϯ2.4% versus females: 23.0Ϯ3.2% change in renal blood flow at 300 ng/kg per minute versus baseline; PϽ0.01). In addition, AT 2 R stimulation significantly increased sodium and water excretion to a similar extent in males and females (P Group ϭ0.05 and 0.005). However, there was no significant change in glomerular filtration rate in either sex, suggesting that altered tubular function may be responsible for AT 2 R-induced natriuresis rather than hemodynamic effects. Taken together, this study provides evidence that direct AT 2 R stimulation produces vasodilatory and natriuretic effects in the male and female kidney. The AT 2 R may, therefore, represent a valuable therapeutic target for the treatment of renal and cardiovascular diseases in both men and women. Key Words: angiotensin type 2 receptor Ⅲ compound 21 Ⅲ sex differences Ⅲ hypertension Ⅲ natriuresis Ⅲ renal blood flow B efore menopause, women are protected from hypertension and cardiovascular disease relative to men. However, this protection weakens after menopause, and ultimately the prevalence of hypertension in women exceeds that of men. 1 Alarmingly, sex-related differences have also been reported in the efficacy of current cardiovascular therapies, 2,3 with poorer treatment outcomes commonly reported in women. 3 The development of sex-specific approaches for the treatment of hypertension and cardiovascular disease is, therefore, of utmost importance.It is well established that the kidney plays a central role in arterial pressure control. The regulation of sodium excretion by the kidney is critical to the long-term regulation of arterial pressure given its influence on body fluid volume homeostasis. 4 In response to a rise in arterial pressure, sodium and water excretion is increased to reduce extracellular fluid volume and to restore arterial pressure to normal. Abnormal renal excretory function is, therefore, recognized as a key contributor to the development of hypertension. 5The renin-angiotensin system (RAS) plays a pivotal role in the re...

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“…19 In the current study, basal mRNA gene expression levels of AT 1a R were not different between male and female rats, consistent with previous work. 20 To date there is confusion as to the exact role and contribution of the AT 1b R to the global AT 1 R response, data that are required to better interpret this finding. In contrast, basal left ventricular expression and renal AT 2 R mRNA expression were markedly greater in females as compared with males.…”

Section: Discussionmentioning

confidence: 99%

Enhanced Angiotensin II Type 2 Receptor Mechanisms Mediate Decreases in Arterial Pressure Attributable to Chronic Low-Dose Angiotensin II in Female Rats

et al. 2008

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Abstract-The renin-angiotensin system is a far more complex enzymatic cascade than realized previously. Mounting evidence suggests sex-specific differences in the regulation of the renin-angiotensin system and arterial pressure. We examined the hemodynamic responses, angiotensin II receptor subtypes, and angiotensin-converting enzyme 2 gene expression levels after graded doses of angiotensin II in males and females. Mean arterial pressure was measured via telemetry in male and female rats in response to a 2-week infusion of vehicle, low-dose (50 ng/kg per minute SC) or high-dose (400 ng/kg per minute SC) angiotensin II. The effect of concurrent infusion of the angiotensin II type 2 receptor (AT 2 R) blocker (PD123319) was also examined. The arterial pressure response to high-dose angiotensin II was attenuated in females compared with males (24Ϯ8 mm Hg versus 42Ϯ5 mm Hg; P for the interaction between sex and treatment Ͻ0.002). Remarkably, low-dose angiotensin II decreased arterial pressure (11Ϯ4 mm Hg; P for the interaction between sex and treatment Ͻ0.02) at a dose that did not have an effect in males. This decrease in arterial pressure in females was abolished by AT 2 R blockade. Renal AT 2 R, angiotensin-converting enzyme 2, and left ventricular AT 2 R mRNA gene expressions were markedly greater in females than in males with a renal angiotensin II type 1a receptor:AT 2 R ratio of Ϸ1 in females. Angiotensin II infusion did not affect renal AT 2 R mRNA expression but resulted in significantly less left ventricular mRNA expression. Renal angiotensin-converting enzyme 2 mRNA expression levels were greater in females than in males treated with high-dose angiotensin II (Ϸ2.5 fold; P for the interaction between sex and treatment Ͻ0.05). In females, enhancement of the vasodilatory arm of the renin-angiotensin system, in particular, AT 2 R and angiotensin-converting enzyme 2 mRNA expression, may contribute to the sex-specific differences in response to renin-angiotensin system activation. (Hypertension. 2008;52:666-671.)Key Words: basic science Ⅲ gender differences Ⅲ gene expression/regulation Ⅲ hypertension Ⅲ angiotensin receptors C ardiovascular disease is the leading cause of death in the Western world, and, contrary to popular belief, mortality rates for cardiovascular disease are greater in women than men. 1,2 Significant differences in survival after a heart attack have been revealed, with 42% of women who experience heart attacks dying within 1 year, compared with 24% of men. 2 The reasons for these differences in outcomes are unknown but require urgent explanation.Hypertension is a major risk factor for cardiovascular disease, with the renin-angiotensin system (RAS) playing a predominant role in the regulation of arterial pressure in both sexes. The potent end product, angiotensin II (Ang II), acts via 2 main subtypes of receptors responsible for vasoconstriction, sodium reabsorption and cell proliferation (in the rodents there are 2 further subtypes: type 1a [AT 1a R] and type 1b [AT 1b R]), as well as vasodil...

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Estrogen upregulates renal angiotensin II AT1 and AT2 receptors in the rat

Cited by 107 publications

References 43 publications

Gender Differences in Pressure-Natriuresis and Renal Autoregulation

Gender Differences in Pressure-Natriuresis and Renal Autoregulation

Sex-Specific Influence of Angiotensin Type 2 Receptor Stimulation on Renal Function

Enhanced Angiotensin II Type 2 Receptor Mechanisms Mediate Decreases in Arterial Pressure Attributable to Chronic Low-Dose Angiotensin II in Female Rats

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