Gender Differences in Pressure-Natriuresis and Renal Autoregulation

Hilliard, Lucinda M; Nematbakhsh, Mehdi; Kett, Michelle M; Teichman, Elleesha; Sampson, Amanda K.; Widdop, Robert E; Evans, Roger G.; Denton, Kate M.

doi:10.1161/hypertensionaha.110.166827

Cited by 115 publications

(125 citation statements)

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“…7 This observation of a sex-specific renal vascular response to C21 in the present study is consistent with our previous observations in rodents that AT 2 R plays a greater functional role in female than in male renal vasculature, providing protection against the vasoconstrictor effects of AngII. 5,6,8 Furthermore, our data support the notion that differences in the renal response to C21 between male and female SHRs is attributable to sex differences in renal AT 2 R expression. We observed significantly greater basal AT 2 R mRNA expression in the kidneys of female SHRs as compared with male SHRs, in agreement with the previous findings of Silva-Antonialli et al 2 In addition, although we observed significantly greater renal angiotensin type 1a receptor expression in female SHRs as compared with their male counterparts, the relative AT 2 R-to-AT 1 R ratio was much greater in female than in male SHRs, although such sex differences in basal renal AT 1 R or AT 2 R mRNA expression are not always reported.…”

Section: Discussionsupporting

confidence: 84%

“…Acute systemic blockade of AT 2 R shifted the pressure-natriuresis relationship rightwards in both female and male rats. 5 Moreover, AT 2 R blockade blunted the autoregulation of renal blood flow (RBF) and glomerular filtration rate (GFR) at low renal perfusion pressures and enhanced the renal vasoconstrictor response to AngII in female rats only. 5 This led to our conclusion that AT 2 R modulates sodium excretion in both sexes and may contribute to the mechanisms by which female sex is protected against AngII-induced vascular alterations and hypertension.…”

mentioning

confidence: 99%

“…5 Moreover, AT 2 R blockade blunted the autoregulation of renal blood flow (RBF) and glomerular filtration rate (GFR) at low renal perfusion pressures and enhanced the renal vasoconstrictor response to AngII in female rats only. 5 This led to our conclusion that AT 2 R modulates sodium excretion in both sexes and may contribute to the mechanisms by which female sex is protected against AngII-induced vascular alterations and hypertension. In addition, we recently demonstrated that acute administration of the selective AT 2 R agonist, compound 21 (C21), produced significant vasodilatory and natriuretic effects in the kidney of both female and male normotensive rats.…”

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Angiotensin Type 2 Receptor Stimulation Increases Renal Function in Female, but Not Male, Spontaneously Hypertensive Rats

et al. 2014

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378T he development and progression of hypertension differs between men and women. Before menopause, arterial pressure is lower in women than in men of similar age. 1 However, after menopause, this cardioprotection in women is lost, and a higher proportion of women than men have hypertension after the age of 65 years.1 Similar differences in arterial pressure control have been observed in other mammalian species, including spontaneously hypertensive rats (SHRs). 2,3These sex-related differences in the development of hypertension have been strongly linked to sexual dimorphism in the renin-angiotensin system (RAS), which plays a pivotal role in the long-term regulation of arterial pressure. 3,4 Classically, angiotensin II (AngII) acts via the angiotensin type 1 receptor (AT 1 R) to cause vasoconstriction and sodium retention. Activation of the pressor RAS is a key mediator in the development of hypertension, and drugs that target this system are mainstays of current antihypertensive therapy. More recently, a depressor arm of the RAS has been recognized, which counterbalances the actions of AngII at AT 1 R. AngII together with other biologically active angiotensin peptides, including angiotensin (1-7) and angiotensin III, interact with angiotensin type 2 receptor (AT 2 R) to evoke vasodilatation and natriuresis. Overwhelming evidence suggests that the depressor RAS is upregulated in women by estrogen, and this contributes to sexual dimorphism in arterial pressure control.3,4 It is, therefore, plausible that enhancement of the depressor RAS, and in particular the AT 2 R, may represent a novel therapeutic target in the treatment of hypertension, particularly in women.Our recent data from normotensive rats support the notion that AT 2 R plays an integral, yet sexually dimorphic, functional Abstract-Accumulating evidence suggests that the protective pathways of the renin-angiotensin system are enhanced in women, including the angiotensin type 2 receptor (AT 2 R), which mediates vasodilatory and natriuretic effects. To provide insight into the sex-specific ability of pharmacological AT 2 R stimulation to modulate renal function in hypertension, we examined the influence of the AT 2 R agonist, compound 21 (100-300 ng/kg per minute), on renal function in 18-to 19-weekold anesthetized male and female spontaneously hypertensive rats. AT 2 R stimulation significantly increased renal blood flow in female hypertensive rats (P Treatment <0.001), without influencing arterial pressure. For example, at 300 ng/kg per minute of compound 21, renal blood flow increased by 14.3±1.8% from baseline. Furthermore, at 300 ng/kg per minute of compound 21, a significant increase in urinary sodium excretion was observed in female hypertensive rats (+180±59% from baseline; P<0.05 versus vehicle-treated rats). This was seen in the absence of any major change in glomerular filtration rate, indicating that the natriuretic effects of AT 2 R stimulation were likely the result of altered renal tubular function. Conversely, we did not observe any sign...

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Section: Discussionsupporting

confidence: 84%

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confidence: 99%

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confidence: 99%

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Angiotensin Type 2 Receptor Stimulation Increases Renal Function in Female, but Not Male, Spontaneously Hypertensive Rats

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“…We have also recently reported that the AT 2 R has a significant role in the control of renal function. 7,8 We showed that direct AT 2 R stimulation using C21 has a pronounced influence on renal excretory and hemodynamic function, albeit in normotensive rats using a substantially lower dose (0.028 mg kg À1 per minute). 8 Remarkably, in both studies, the renal response to C21 was observed without any inhibition of AT 1 R function, demonstrating the ability of AT 2 R agonism to directly modulate renal function.…”

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confidence: 92%

“…We have also recently reported that the AT 2 R has a significant role in the control of renal function. 7,8 …”

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The angiotensin type 2 receptor weighs in on obesity: a promising therapeutic target?

Hilliard

Denton

2012

Hypertens Res

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Excessive weight gain is one of the leading causes of increased arterial pressure in human essential hypertension. Given the rising obesity 'epidemic' , there is an urgent need to further our understanding of the mechanisms responsible for weight-related changes in arterial pressure in order to improve treatment strategies. Extensive evidence exists that obesity-related hypertension is strongly associated with renal dysfunction. Like other forms of hypertension, the increased arterial pressure associated with obesity is accompanied by a shift in the renal pressure-natriuresis relationship, such that increased arterial pressure is required to maintain sodium homeostasis. 1 This impairment in renal excretory function in obesity is initially thought to be primarily due to enhanced tubular reabsorption of sodium, since glomerular filtration rate and renal blood flow are actually increased. 1 The renin-angiotensin system (RAS) has a pivotal role in the long-term regulation of arterial pressure by the kidney. Overactivity of the RAS is considered to have a major role in mediating obesity-related sodium retention. The principle effector peptide of the RAS, angiotensin II (AngII), elicits its effects via two main receptor types with equal affinity. 2 The majority of the classically recognized actions of AngII are mediated by the angiotensin type 1 receptor (AT 1 R) including vasoconstriction, sodium reabsorption and vascular growth. In contrast, the angiotensin type 2 receptor (AT 2 R) directly opposes these pressor actions of AngII, by promoting vasodilation and natriuresis, as well as antiproliferative and antigrowth effects. Additionally, other biologically active angiotensin metabolites have been identified in recent years, which can also directly oppose AT 1 R responses through their interaction with the AT 2 R and elicit natriuretic responses from the kidney, 2 including angiotensin III (AngIII) and angiotensin (1-7) (Figure 1). In fact, accumulating evidence suggests that AngIII, rather than AngII, is actually the preferred ligand of the AT 2 R in the kidney. 3 In obesity, multiple RAS components are reported to be significantly increased, including plasma renin activity, angiotensinogen, angiotensin-converting enzyme (ACE) and plasma AngII. 1 In particular, increased AngII-induced renal AT 1 R activation is thought to be a key mechanism that contributes to the increased renal sodium retention and the resetting of pressure-natriuresis, leading to increased arterial pressure. Much emphasis has subsequently been placed on reducing the deleterious effects of the AT 1 R to improve sodium excretion and reduce arterial pressure in obesity, through the use of angiotensin receptor blockers and ACE inhibitors. Numerous studies have shown that AT 1 R antagonism and ACE inhibition elicit natriuretic effects and arterial pressure reduction in obese humans and animal models, 1 providing direct evidence that the antinatriuretic actions of endogenous AngII are exaggerated in obesity. However, more recently the role of the AT 2 ...

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Compromised regulation of the collecting duct ENaC activity in mice lacking AT_1a receptor

Mamenko

Zaika

Tomilin

et al. 2018

Journal Cellular Physiology

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ENaC-mediated sodium reabsorption in the collecting duct (CD) is a critical determinant of urinary sodium excretion. Existing evidence suggest direct stimulatory actions of Angiotensin II (Ang II) on ENaC in the CD, independently of the aldosterone-mineralocorticoid receptor (MR) signaling. Deletion of the major renal AT receptor isoform, AT R, decreases blood pressure and reduces ENaC abundance despite elevated aldosterone levels. The mechanism of this insufficient compensation is not known. Here, we used patch clamp electrophysiology in freshly isolated split-opened CDs to investigate how AT R dysfunction compromises functional ENaC activity and its regulation by dietary salt intake. Ang II had no effect on ENaC activity in CDs from AT R -/- mice suggesting no complementary contribution of AT receptors. We next found that AT R deficient mice had lower ENaC activity when fed with low (<0.01% Na ) and regular (0.32% Na ) but not with high (∼2% Na ) salt diet, when compared to the respective values obtained in Wild type (WT) animals. Inhibition of AT R with losartan in wild-type animals reproduces the effects of genetic ablation of AT R on ENaC activity arguing against contribution of developmental factors. Interestingly, manipulation with aldosterone-MR signaling via deoxycosterone acetate (DOCA) and spironolactone had much reduced influence on ENaC activity upon AT R deletion. Consistently, AT R -/- mice have a markedly diminished MR abundance in cytosol. Overall, we conclude that AT R deficiency elicits a complex inhibitory effect on ENaC activity by attenuating ENaC P and precluding adequate compensation via aldosterone cascade due to decreased MR availability.

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Gender Differences in Pressure-Natriuresis and Renal Autoregulation

Cited by 115 publications

References 40 publications

Angiotensin Type 2 Receptor Stimulation Increases Renal Function in Female, but Not Male, Spontaneously Hypertensive Rats

Angiotensin Type 2 Receptor Stimulation Increases Renal Function in Female, but Not Male, Spontaneously Hypertensive Rats

The angiotensin type 2 receptor weighs in on obesity: a promising therapeutic target?

Compromised regulation of the collecting duct ENaC activity in mice lacking AT_1a receptor

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Gender Differences in Pressure-Natriuresis and Renal Autoregulation

Cited by 115 publications

References 40 publications

Angiotensin Type 2 Receptor Stimulation Increases Renal Function in Female, but Not Male, Spontaneously Hypertensive Rats

Angiotensin Type 2 Receptor Stimulation Increases Renal Function in Female, but Not Male, Spontaneously Hypertensive Rats

The angiotensin type 2 receptor weighs in on obesity: a promising therapeutic target?

Compromised regulation of the collecting duct ENaC activity in mice lacking AT1a receptor

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Compromised regulation of the collecting duct ENaC activity in mice lacking AT_1a receptor