scholarly journals In Aged Females, the Enhanced Pressor Response to Angiotensin II Is Attenuated By Estrogen Replacement via an Angiotensin Type 2 Receptor-Mediated Mechanism

Hypertension ◽  
2021 ◽  
Author(s):  
Giannie Barsha ◽  
Katrina M. Mirabito Colafella ◽  
Sarah L. Walton ◽  
Tracey A. Gaspari ◽  
Iresha Spizzo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Arterial Pressure ◽  
Pressor Response ◽  
Ang Ii ◽  
Estrogen Replacement ◽  
Female Mice ◽  
Adult Females ◽  
Angiotensin Type 2 Receptor ◽  
Angiotensin Type

Loss of ovarian hormones following menopause contributes to the rise in cardiovascular risk with age. Estrogen plays a protective role against hypertension and end-organ damage by modulating the depressor actions of the AT 2 R (angiotensin type 2 receptor). Our aim was to determine whether estrogen replacement in aged female mice can lower arterial pressure, improve endothelial function, and reduce organ fibrosis via an AT 2 R-mediated mechanism. Mean arterial pressure was measured via radiotelemetry in ovary-intact adult (3–4-month-old), aged (16–18-month-old; reproductively senescent) and aged–17β-estradiol (E 2 )–treated (3 µg/day SC) female mice, which were administered vehicle, Ang II (angiotensin II; 600 ng/[kg·min] SC) or Ang II+PD123319 (AT 2 R antagonist; 3 mg/[kg·day SC). On day 21 of treatment, aortic endothelium-dependent relaxation and cardiac and renal tissue (fibrosis and gene expression) were analyzed. Basal mean arterial pressure was lower in E 2 -treated aged mice (89±1 mm Hg, n=20) relative to aged controls (94±1 mm Hg; n=18, P =0.002). The Ang II pressor response was enhanced by ≈20 mm Hg in aged compared with adult females ( P =0.01). E 2 -treatment reduced the Ang II pressor response in aged females ( P =0.002), an effect that was reversed by PD123319 in the aged E 2 –Ang II group ( P =0.0009). E 2 -treatment increased renal AT 2 R (≈6-fold; P <0.0001) and MasR (Mas oncoreceptor; 2–3-fold, P <0.05) gene expression in aged females. However, neither Ang II–induced endothelial dysfunction nor the age-related increase in renal and cardiac fibrosis was restored by E 2 -treatment in aged female mice. In conclusion, estrogen replacement in aged females may reduce arterial pressure to levels observed in adult females, via an AT 2 R-mediated renal mechanism.

Abstract 052: Chronic Angiotensin Type 2 Receptor Stimulation Abolishes the Sex-difference in Ang II-induced Hypertension

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Katrina M Mirabito Colafella ◽  
Lucinda M Hilliard ◽  
Donna L Ralph ◽  
Jasmine S Manwani ◽  
Tracey Gaspari ◽  
...  
Keyword(s):  
Arterial Pressure ◽  
Pressor Response ◽  
Receptor Expression ◽  
Female Mice ◽  
Sodium Transporters ◽  
R Ratio ◽  
Angiotensin Type 2 Receptor ◽  
Induced Hypertension ◽  
Angiotensin Type

Arterial pressure is age and sex dependent. The angiotensin type 2 receptor (AT 2 R) plays a greater role in the regulation of arterial pressure and renal function in adult females than age-matched males and aging females. In the present study, we investigated the effect of chronic AT 2 R stimulation using the AT 2 R agonist, compound 21 (C21), to attenuate the hypertensive effects of AngII. Mean arterial pressure (MAP) was measured via radiotelemetry in 14 week old male and female mice treated with vehicle, AngII (36 μg/kg/hr), C21 (18 μg/kg/hr), AngII+C21 or AngII+C21 plus PD123319 (AT 2 R antagonist; 125 μg/kg/hr) for 21 days. At the end of the treatment, renal excretory function, angiotensin receptor expression and sodium transporter profiles were assessed. In agreement with previous studies, the pressor response to AngII was greater in male than female mice (35±3 vs 20±4 mmHg respectively, P<0.05). There was no effect of C21 treatment alone on MAP nor did C21 alter the pressor response to AngII in females. However, in males, C21 blunted the pressor response to AngII such that MAP was similar between AngII+C21 males, AngII females and AngII+C21 females (18±2, 20±4 and 17±4 mmHg on day 21, respectively). Co-infusion of PD123319 restored the normal pressor response to AngII in males. Conversely, in females, treatment with AngII+PD123319 or AngII+C21+PD123319 enhanced the pressor response to AngII by ~20 mmHg, to a level seen in AngII males. The renal AT 2 R/AT 1 R ratio was greater in female than male mice and was not affected by treatment. Vehicle treated females had lower proximal versus distal Na+ transporter abundance than males. AngII-treatment increased NCC in both sexes, while proximal and loop transporters (NHE, NHE3-P, NaPi2 and NKCC2) decreased in males only. Treatment with C21 alone did not significantly affect sodium transporters. In males, AngII+C21treatment increased distal transporters and this effect was reversed by PD123319. Conversely, in females, C21 blunted the AngII effect on sodium transporters (claudin-2, NKCC-P, NCC-P and ENaC). Our novel data demonstrate that chronic AT 2 R stimulation attenuates AngII-induced hypertension in adult males, but not females. Thus, AT 2 R agonists may be a novel antihypertensive therapy for males and ageing females.

Abstract P288: Systemic Administration of an Angiotensin Type-2 Receptor Agonist Decreases Renal Regulatory T Cells

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Ellen E Gillis ◽  
Jennifer C Sullivan
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Critical Role ◽  
High Dose ◽  
Ang Ii ◽  
Osmotic Minipump ◽  
Angiotensin Type 2 Receptor ◽  
Angiotensin Type

There is increasing evidence supporting a critical role of the immune system in the development of hypertension. Our lab has previously reported sex differences in the renal T cell profile in both Spontaneously Hypertensive Rats (SHR) and Angiotensin II (Ang II) models of hypertension, with females having more anti-inflammatory regulatory T cells (Tregs) than males. Ang II has a well-defined role in the activation of pro-inflammatory T cells in hypertension via the angiotensin type-1 receptor (AT1R). Less is known about the role of the angiotensin type-2 receptor (AT2R) in the regulation of immune cells, although the AT2R has been shown to be cardioprotective and AT2R expression is greater in females than males. Based on the potential anti-hypertensive role of AT2Rs, we hypothesized that administration of an AT2R agonist, Compound 21 (C21), would increase renal Tregs, and this increase would be greater in females due to greater AT2R expression. Male and female SHR (10 weeks of age, n=3-4) were implanted with telemetry units for continuous monitoring of mean arterial pressure (MAP). Following 10 days of recovery, baseline MAP was recorded for 5 days. Rats were then divided into the following treatment groups: surgical controls, low dose C21 (150 ng/kg/min, sc by osmotic minipump), high dose C21 (300 ng/kg/min, sc by osmotic minipump). Kidneys were harvested after 2 weeks of treatment and flow cytometry was performed on whole kidney homogenates. MAP was not altered by C21 treatment in males (137±4 vs 134±4 vs 134±4 mmHg; n.s.) or females (128±2 vs 136±5 vs 134±4 mmHg; n.s.). Interestingly, despite having no effect on MAP, there was a significant decrease in renal CD3 + CD4 + FoxP3 + Tregs in females following both low and high doses of C21 (data expressed as % CD3 + CD4 + cells: 6±0.6 vs 3±0.6 vs 3.5±1.3 %, respectively; p=0.02). Tregs decrease in males following the high dose of C21 only (data expressed as % CD3 + CD4 + cells: 3.3±0.3 vs 3.3±0.5 vs 1.7±0.7 %, respectively; p=0.05). Total CD3 + T cells, CD3 + CD4 + T cells, and Th17 cells were not altered by C21 treatment. In conclusion, AT2R activation suppresses renal Tregs, and females are more sensitive than males. These data suggest a novel role for AT2R regulation in the kidney in hypertension.

scholarly journals Angiotensin type 2 receptor in pancreatic islets of adult rats: a novel insulinotropic mediator

2013 ◽  
Vol 305 (10) ◽  
pp. E1281-E1291 ◽  
Author(s):  
Chunhong Shao ◽  
Irving H. Zucker ◽  
Lie Gao
Keyword(s):  
Pancreatic Islets ◽  
Combined Treatment ◽  
Insulin Biosynthesis ◽  
In Vitro Experiments ◽  
Ang Ii ◽  
Adult Rats ◽  
Angiotensin Type 2 Receptor ◽  
Angiotensin Type

In the present study, we evaluated the relative abundance of angiotensin type 2 receptor (AT2R) protein in various tissues of adult rats. We found that pancreatic islets expressed the highest AT2R protein compared with all other tissues. Accordingly, we then determined the functional significance of AT2R in the endocrine pancreas in in vivo and in vitro experiments by using angiotensin II (ANG II) alone, losartan (Los; AT1R antagonist), compound 21 (C21; AT2R agonist), and PD-123319 (PD; AT2R antagonist). Experiments carried out in rats indicated that, 1) ANG II treatment significantly increased plasma insulin concentration (1.51 ± 0.20 vs. 0.82 ± 0.14 ng/ml, n = 7, P < 0.05) in the fed state. This insulinotropic effect was further augmented by combined treatment with ANG II + Los (2.31 ± 0.25 ng/ml, n = 7, P < 0.01). C21 also elevated insulin levels (2.13 ± 0.20 ng/ml, n = 7, P < 0.01), which was completely abolished by PD. 2) ANG II impaired glucose tolerance, whereas ANG II + Los or C21 improved this function. 3) All treated rats displayed an enhanced insulin secretory response to a glucose challenge. 4) All treated rats displayed upregulated proinsulin 2 mRNA and insulin protein expression in the pancreas. In in vitro experiments using INS-1E cells and isolated rat islets, we found that AT2R activation significantly improved insulin biosynthesis and secretion. These results suggest that the AT2R functions as an insulinotropic mediator. AT2R and its downstream signaling pathways may be potential therapeutic targets for diabetes.

scholarly journals Pressor responsiveness to angiotensin II in female mice is enhanced with age: role of the angiotensin type 2 receptor

2014 ◽  
Vol 5 (1) ◽  
Author(s):  
Katrina M Mirabito ◽  
Lucinda M Hilliard ◽  
Geoffrey A Head ◽  
Robert E Widdop ◽  
Kate M Denton
Keyword(s):  
Angiotensin Ii ◽  
Female Mice ◽  
Angiotensin Type 2 Receptor ◽  
Angiotensin Type

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

2014 ◽  
Vol 307 (8) ◽  
pp. F901-F907 ◽  
Author(s):  
Katrina M. Mirabito ◽  
Lucinda M. Hilliard ◽  
Michelle M. Kett ◽  
Russell D. Brown ◽  
Sean C. Booth ◽  
...  
Keyword(s):  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
Receptor Expression ◽  
Dependent Manner ◽  
Wild Type ◽  
Age Related ◽  
Angiotensin Type 2 Receptor ◽  
Pressure Natriuresis ◽  
Angiotensin Type

Sex hormones regulate the renin-angiotensin system. For example, estrogen enhances expression of the angiotensin type 2 receptor. We hypothesized that activation of the angiotensin type 2 receptor shifts the chronic pressure-natriuresis relationship leftward in females compared with males and that this effect is lost with age. Mean arterial pressure was measured by radiotelemetry in adult (4 mo old) and aged (14 mo old) wild-type and angiotensin type 2 receptor knockout male and female mice. Chronic pressure-natriuresis curves were constructed while mice were maintained on a normal-salt (0.26%) diet and following 6 days of high salt (5.0%) diet. Mean arterial pressure was lower in adult wild-type females than males (88 ± 1 and 97 ± 1 mmHg, respectively), a difference that was maintained with age, but was absent in adult knockout mice. In wild-type females, the chronic pressure-natriuresis relationship was shifted leftward compared with knockout females, an effect that was lost with age. In males, the chronic pressure-natriuresis relationship was not influenced by angiotensin type 2 receptor deficiency. Compared with age-matched females, the chronic pressure-natriuresis relationships in male mice were shifted rightward. Renal expression of the angiotensin type 2 receptor was fourfold greater in adult wild-type females than males. With age, the angiotensin type 2 receptor-to-angiotensin type 1 receptor balance was reduced in females. Conversely, in males, angiotensin receptor expression did not vary significantly with age. In conclusion, the angiotensin type 2 receptor modulates the chronic pressure-natriuresis relationship in an age- and sex-dependent manner.

scholarly journals Signals from the AT2 (Angiotensin Type 2) Receptor of Angiotensin II Inhibit p21ras and Activate MAPK (Mitogen-Activated Protein Kinase) to Induce Morphological Neuronal Differentiation in NG108–15 Cells

1999 ◽  
Vol 13 (9) ◽  
pp. 1615-1626 ◽  
Author(s):  
Louis Gendron∗ ◽  
Liette Laflamme∗ ◽  
Nathalie Rivard ◽  
Claude Asselin ◽  
Marcel D. Payet ◽  
...  
Keyword(s):  
Neurite Outgrowth ◽  
Morphological Differentiation ◽  
Mitogen Activated Protein Kinase ◽  
Ang Ii ◽  
Mapk Activity ◽  
Angiotensin Type 2 Receptor ◽  
Mitogen Activated Protein ◽  
Angiotensin Type ◽  
Stimulation Of

Abstract In a previous study, we had shown that activation of the AT2 (angiotensin type 2) receptor of angiotensin II (Ang II) induced morphological differentiation of the neuronal cell line NG108–15. In the present study, we investigated the nature of the possible intracellular mediators involved in the AT2 effect. We found that stimulation of AT2 receptors in NG108–15 cells resulted in time-dependent modulation of tyrosine phosphorylation of a number of cytoplasmic proteins. Stimulation of NG108–15 cells with Ang II induced a decrease in GTP-bound p21ras but a sustained increase in the activity of p42mapk and p44mapk as well as neurite outgrowth. Similarly, neurite elongation, increased polymerized tubulin levels, and increased mitogen-activated protein kinase (MAPK) activity were also observed in a stably transfected NG108–15 cell line expressing the dominant-negative mutant of p21ras, RasN17. These results support the observation that inhibition of p21ras did not impair the effect of Ang II on its ability to stimulate MAPK activity. While 10 μm of the MEK inhibitor, PD98059, only moderately affected elongation, 50 μm PD98059 completely blocked the Ang II- and the RasN17-mediated induction of neurite outgrowth. These results demonstrate that some of the events associated with the AT2 receptor-induced neuronal morphological differentiation of NG108–15 cells not only include inhibition of p21ras but an increase in MAPK activity as well, which is essential for neurite outgrowth.

The angiotensin type 2 receptor in the human adrenocortical zona glomerulosa and in aldosterone-producing adenoma: low expression and no functional role

2018 ◽  
Vol 132 (6) ◽  
pp. 627-640 ◽  
Author(s):  
Paul-Emmanuel Vanderriele ◽  
Brasilina Caroccia ◽  
Teresa Maria Seccia ◽  
Maria Piazza ◽  
Livia Lenzini ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Lines ◽  
Hormone Secretion ◽  
Zona Glomerulosa ◽  
Ang Ii ◽  
Aldosterone Synthase ◽  
Adjacent Tissue ◽  
Angiotensin Type 2 Receptor ◽  
Aldosterone Producing Adenoma

The angiotensin II (Ang II) type 2 receptor (AT2R) and the angiotensin-(1–7) (Ang-(1–7)) receptor (MasR) play a cardiovascular protective role by counter-regulating Ang II type 1 receptor (AT1R)-mediated effects, but whether this involves blunting of adrenocortical hormone secretion is unknown. We investigated the presence of AT1R, AT2R, and MasR in aldosterone-producing adenoma (APA), a condition featuring hyperaldosteronism, and in APA-adjacent tissue. The effect of Compound 21 (C21), an AT2R agonist, on CYP11B1 (cortisol synthase) and CYP11B2 (aldosterone synthase) gene expression in NCI-H295R and HAC15 cell lines, and in APA and APA-adjacent tissue, was also assessed using the AT1R antagonist irbesartan to ascertain the specificity of C21 effect. We found that the AT1R, AT2R, and MasR were expressed in APA and APA-adjacent tissue, albeit heterogeneously. The gene expression of AT1R and AT2R was lower, and that of the MasR higher in APAs than in APA-adjacent tissue. In steroid-producing NCI-H295R and HAC15 cell lines, and in APA and APA-adjacent tissue, C21 was ineffective at nanomolar concentrations, but increased CYP11B1 and CYP11B2 gene expression at micromolar concentrations through AT1R, as this effect was blunted by irbesartan. The scant expression of the AT2R, along with the lack of any effect of C21 at low concentrations on CYP11B2, do not support the contention that the protective arm of renin–angiotensin system (RAS) blunts aldosterone synthase in the normal adrenal cortex and primary aldosteronism.

scholarly journals Role of Inflammation and the Angiotensin Type 2 Receptor in the Regulation of Arterial Pressure During Pregnancy in Mice

Hypertension ◽  
2014 ◽  
Vol 64 (3) ◽  
pp. 626-631 ◽  
Author(s):  
Katrina M. Mirabito ◽  
Lucinda M. Hilliard ◽  
Zihui Wei ◽  
Chris Tikellis ◽  
Robert E. Widdop ◽  
...  
Keyword(s):  
Arterial Pressure ◽  
Angiotensin Type 2 Receptor ◽  
Angiotensin Type
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