Angiotensin II type 2 receptor mediates sex differences in mice renal interlobar arteries response to angiotensin II

Viegas, Vinícius Urbano; Liu, Zhi Z; Nikitina, Tatiana; Perlewitz, Andrea; Zavaritskaya, Olga; Schlichting, Jeremias; Persson, Pontus B.; Regitz‐Zagrosek, Vera; Patzak, Andreas; Sendeski, Mauricio

doi:10.1097/hjh.0b013e32835731dd

Cited by 8 publications

(7 citation statements)

References 46 publications

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“…However, the increases in U Na V observed in both males and females in response to β-Pro 7 -Ang III were not dependent on sex. These findings also corroborate our previous findings using the non-peptide AT 2 R agonist, Compound 21 [12], and substantiate our previous reports, and that of others, that the role of the AT 2 R in the renal vasculature is enhanced in females [13,15,16]. As we have discussed in detail elsewhere [1,17,18], the sex-specific role of the AT 2 R is likely attributable to direct effects of gonadal hormones and genes encoded on the sex chromosomes.…”

Section: Discussionsupporting

confidence: 92%

Renal functional effects of the highly selective AT2R agonist, β-Pro7 Ang III, in normotensive rats

et al. 2020

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Recently, we designed a group of peptides by sequential substitution of the naturally occurring α-amino acid throughout the Ang III peptide sequence with the corresponding β-amino acid. β-Amino acid substitution at the proline residue of Ang III (β-Pro7-Ang III) resulted in a highly selective AT2R ligand, demonstrating remarkable selectivity for the AT2R in both binding and functional studies. To provide additional functional evidence for the suitability of β-Pro7 Ang III as a novel AT2R agonist, we tested effects of acute systemic administration of β-Pro7-Ang III on renal hemodynamic and excretory function in anesthetized normotensive male and female rats. We also compared the natriuretic effects of acute intrarenal administration of native Ang III and β-Pro7-Ang III in the presence of systemic AT1R blockade in anesthetized female rats to allow for the differentiation of systemic versus direct intrarenal natriuretic actions of β-Pro7-Ang III. In both male and female rats, acute systemic administration of β-Pro7-Ang III elicited renal vasodilatation and natriuresis. Notably, greater renal vasodilatory effects were observed in female versus male rats at the highest dose of β-Pro7-Ang III administered. Moreover, intra-renal administration of β-Pro7-Ang III produced significant natriuretic effects in female rats and, like Ang III, evoked AT2R translocation to the apical plasma membrane in renal proximal tubular cells. Taken together, our findings support the use of β-Pro7-Ang III as a novel AT2R agonist and experimental tool for exploring AT2R function and its potential as a therapeutic target. Furthermore, our findings provide further evidence of a sex-specific influence of AT2R stimulation on renal function.

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Section: Discussionsupporting

confidence: 92%

Renal functional effects of the highly selective AT2R agonist, β-Pro7 Ang III, in normotensive rats

et al. 2020

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“…Key vascular regulatory pathways are balanced towards cardioprotection in females between puberty and menopause, after which the balance shifts to become pro-hypertensive [52]. It is likely the differences between our findings and Viegas et al [51] is a factor of ageing as the rats used in this study were 12 months of age, considered to be middle age in the Sprague-Dawley where early reproductive senescence may arise [27].…”

Section: Discussionmentioning

confidence: 77%

“…Of particular interest, there are known sex differences in the response of the renal arteries to angiotensin II in young rodents. A previous study showed renal interlobar arteries from 3-month-old mice contracted significantly less to angiotensin II compared to arteries from age-matched male mice, an effect due to angiotensin type 2 receptor-mediated nitric oxide release in females [51]. Key vascular regulatory pathways are balanced towards cardioprotection in females between puberty and menopause, after which the balance shifts to become pro-hypertensive [52].…”

Section: Discussionmentioning

confidence: 99%

Chronic low alcohol intake during pregnancy programs sex-specific cardiovascular deficits in rats

et al. 2019

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Background Exposure to an adverse environment in early life can have lifelong consequences for risk of cardiovascular disease. Maternal alcohol (ethanol) intake is common and associated with a variety of harmful effects to the fetus. However, examining the effects on the cardiovascular system in adult offspring has largely been neglected. The objectives of this study were to investigate the influence of chronic, low ethanol consumption throughout pregnancy on blood pressure, vascular reactivity and wall stiffness, all key determinants of cardiovascular health, in both male and female rat offspring. Methods Female Sprague-Dawley rats were fed an ad libitum liquid diet ± 6% vol/vol ethanol throughout pregnancy. Male and female offspring were studied at 12 months of age. Arterial pressure, heart rate and locomotor activity were measured over 7 days via radiotelemetry. Renal lobar arteries were isolated and studied using wire and pressure myography. Results Basal mean arterial pressure in female ethanol-exposed rats was reduced by ~ 5–6 mmHg compared to control female offspring, whereas arterial pressure was unaffected in male offspring. Ethanol-exposed offspring had an attenuated pressor response to an acute restraint stress, with this effect most evident in females. Renal artery function was not affected by prenatal ethanol exposure. Conclusions We show for the first time that low level chronic maternal alcohol intake during pregnancy influences arterial pressure in adult offspring in the absence of fetal growth restriction. Electronic supplementary material The online version of this article (10.1186/s13293-019-0235-9) contains supplementary material, which is available to authorized users.

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“…The angiotensin type 2 receptor (AT 2 R) also opposes the pressor actions of the classic Ang II/AT 1 R (12). Despite similar expression levels of the AT 2 R in male and female mice, AT 2 R blockade enhances Ang II-induced renal vasoconstriction in female mice but not in males (37). Thus, the AT 2 R may also be a potential mediator of the sex difference in acute hyperresponsiveness to acute Ang II in growth-restricted rats.…”

Section: Discussionmentioning

confidence: 94%

Sex differences in the enhanced responsiveness to acute angiotensin II in growth-restricted rats: role of fasudil, a Rho kinase inhibitor

Ojeda

Royals

Alexander

2013

American Journal of Physiology-Renal Physiology

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This study tested the hypothesis that Rho kinase contributes to the enhanced pressor response to acute angiotensin II in intact male growth-restricted and gonadectomized female growth-restricted rats. Mean arterial pressure (MAP) and renal function were determined in conscious animals pretreated with enalapril (250 mg/l in drinking water) for 1 wk to block the endogenous renin-angiotensin system and normalize blood pressure (baseline). Blood pressure and renal hemodynamics did not differ at baseline. Acute Ang II (100 ng·kg(-1)·min(-1)) induced a greater increase in MAP and renal vascular resistance and enhanced reduction in glomerular filtration rate in intact male growth-restricted rats compared with intact male controls (P < 0.05). Cotreatment with the Rho kinase inhibitor fasudil (33 μg·kg(-1)·min(-1)) significantly attenuated these hemodynamic changes (P < 0.05), but it did not abolish the differential increase in blood pressure above baseline, suggesting that the impact of intrauterine growth restriction on blood pressure in intact male growth-restricted rats is independent of Rho kinase. Gonadectomy in conjunction with fasudil returned blood pressure back to baseline in male growth-restricted rats, and yet glomerular filtration rate remained significantly reduced (P < 0.05). Thus, these data suggest a role for enhanced renal sensitivity to acute Ang II in the developmental programming of hypertension in male growth-restricted rats. However, inhibition of Rho kinase had no effect on the basal or enhanced increase in blood pressure induced by acute Ang II in the gonadectomized female growth-restricted rat. Therefore, these studies suggest that Rho kinase inhibition exerts a sex-specific effect on blood pressure sensitivity to acute Ang II in growth-restricted rats.

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Angiotensin II type 2 receptor mediates sex differences in mice renal interlobar arteries response to angiotensin II

Abstract: A sex-specific, nitric oxide-mediated effect via angiotensin II type 2 receptors underlies the sex differences in the response of interlobar arteries to angiotensin II. Our findings may help understanding sex differences in renal hemodynamics and blood pressure control.

Cited by 8 publications

References 46 publications

Renal functional effects of the highly selective AT2R agonist, β-Pro7 Ang III, in normotensive rats

Renal functional effects of the highly selective AT2R agonist, β-Pro7 Ang III, in normotensive rats

Chronic low alcohol intake during pregnancy programs sex-specific cardiovascular deficits in rats

Sex differences in the enhanced responsiveness to acute angiotensin II in growth-restricted rats: role of fasudil, a Rho kinase inhibitor

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