Role of angiotensin‐converting enzyme 2 and angiotensin(1–7) in 17β‐oestradiol regulation of renal pathology in renal wrap hypertension in rats

Ji, Hong; Menini, Stefano; Zheng, Wei; Pesce, Carlo; Wu, Xie; Sandberg, Kathryn

doi:10.1113/expphysiol.2007.041392

Cited by 107 publications

(103 citation statements)

References 45 publications

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“…Accordingly, ACE2 mRNA and activity were increased in the kidney and uterus of pregnant animals. [38][39][40][41] In line with these results, Shenoy et al Our study indicates that E2 via down-regulation of ACE and simultaneous induction of ACE2 might modify the atrial responses to stress and could contribute to antiarrhythmic effects. The activated classical RAS and, in particular, increased AngII levels are key mediators of atrial tissue remodeling that might facilitate the development of atrial arrhythmia, like AF.…”

Section: Discussionsupporting

confidence: 74%

Protective regulation of the ACE2/ACE gene expression by estrogen in human atrial tissue from elderly men

Bukowska

Spiller²,

Wolke

et al. 2017

Exp Biol Med (Maywood)

178

183

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The present study demonstrates that estrogen affects the human atrial myocardium and mediates protective actions through estrogen receptors-(ER) dependent signaling. Estrogen substantially modulates the local RAS via downregulation of ACE and simultaneous upregulation of ACE2, AT2R and MAS expression levels. This is indicative of a shift of the classical RAS/ACE axis to the alternative, protective RAS/ACE2 axis. In support of this view, estrogen attenuated the expression of RAS-associated downstream effectors, LOX-1, and ICAM-1. A specific antagonist of ERa reversed the anti-inflammatory and anti-oxidative effects of estrogen in paced and nonpaced atrial tissue slices. In summary, our data demonstrate the existence of protective effects of estrogen in atrial tissue from elderly men which are at least in part, mediated by the regulation of local RAS homeostasis. AbstractData from animal experiments and clinical investigations suggest that components of the renin-angiotensin system are markedly affected by sex hormones. However, whether estrogen affects human atrial myocardium has not been investigated yet. In this study, we determined the effects of estrogen on key components of atrial renin-angiotensin system: angiotensin-converting enzyme, responsible for generation of angiotensin II and angiotensin-converting enzyme 2, counteracting majority of AngII effects, and different renin-angiotensin system receptors, AT1R, AT2R, and MAS. First, the expression levels of estrogen receptors mRNA were determined in right atrial appendages obtained from patients undergoing heart surgery. The amounts of estrogen receptor a and estrogen receptor b mRNA were similar between women (n ¼ 14) and men (n ¼ 10). Atrial tissue slices (350 mm) were prepared from male donors which were exposed to estrogen (1-100 nM; n ¼ 21) or stimulated at 4 Hz for 24 h in the presence or absence of 100 nM estrogen (n ¼ 16), respectively. The administration of estrogen did not change mRNA levels of estrogen receptors, but activated MAP kinases, Erk1/2. Furthermore, estrogen increased the amounts of angiotensin-converting enzyme 2-mRNA (1.89 AE 0.23; P < 0.05) but reduced that of angiotensin-converting enzyme-mRNA (0.78 AE 0.07, P < 0.05). In addition, the transcript levels of AT2R and MAS were upregulated by estrogen. Pacing of tissue slices significantly increased the angiotensin-converting enzyme/angiotensin-converting enzyme 2 ratio at both the mRNA and protein level. During pacing, administration of estrogen substantially lowered the angiotensin-converting enzyme/angiotensin-converting enzyme 2 ratio at the transcript (0.92 AE 0.21 vs. 2.12 AE 0.27 at 4 Hz) and protein level (0.94 AE 0.20 vs. 2.14 AE 0.3 at 4 Hz). Moreover, estrogen elicited anti-inflammatory and anti-oxidative effects on renin-angiotensin system-associated downstream effectors such as pro-oxidative LOX-1 and pro-inflammatory ICAM-1. An antagonist of estrogen receptor a reversed these anti-inflammatory and anti-oxidative effects of estrogen significantly. Overall, our results demo...

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Section: Discussionsupporting

confidence: 74%

Protective regulation of the ACE2/ACE gene expression by estrogen in human atrial tissue from elderly men

Bukowska

Spiller²,

Wolke

et al. 2017

Exp Biol Med (Maywood)

178

183

View full text Add to dashboard Cite

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“…We and others also have shown that female sex hormones upregulate renal and brain ACE2/ANG-(1-7) mRNA expression to provide a protective role against the development of renal wrap-and Aldo/NaCl-induced hypertension (15,31). In the present study, subpressor ANG II treatment mainly increased LT mRNA expression of ACE2 and MasR in intact females.…”

Section: Discussionsupporting

confidence: 49%

Estrogen regulation of the brain renin-angiotensin system in protection against angiotensin II-induced sensitization of hypertension

Xue

Zhang

Beltz

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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This study investigated sex differences in the sensitization of angiotensin (ANG) II-induced hypertension and the role of central estrogen and ANG-(1-7) in this process. Male and female rats were implanted for telemetered blood pressure (BP) recording. A subcutaneous subpressor dose of ANG II was given alone or concurrently with intracerebroventricular estrogen, ANG-(1-7), an ANG-(1-7) receptor antagonist A-779 or vehicle for 1 wk (induction). After a 1-wk rest (delay), a pressor dose of ANG II was given for 2 wk (expression). In males and ovariectomized females, subpressor ANG II had no sustained effect on BP during induction, but produced an enhanced hypertensive response to the subsequent pressor dose of ANG II during expression. Central administration of estrogen or ANG-(1-7) during induction blocked ANG II-induced sensitization. In intact females, subpressor ANG II treatment produced a decrease in BP during induction and delay, and subsequent pressor ANG II treatment given during expression produced only a slight but significant increase in BP. However, central blockade of ANG-(1-7) by intracerebroventricular infusion of A-779 during induction restored the decreased BP observed in females during induction and enhanced the pressor response to the ANG II treatment during expression. RT-PCR analyses indicated that estrogen given during induction upregulated mRNA expression of the renin-angiotensin system (RAS) antihypertensive components, whereas both central estrogen and ANG-(1-7) downregulated mRNA expression of RAS hypertensive components in the lamina terminalis. The results indicate that females are protected from ANG II-induced sensitization through central estrogen and its regulation of brain RAS.

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“…17␤-Estradiol (E 2 ) has been reported to regulate ACE2 expression both in vitro and in vivo (15,20,21). Moreover, results from our laboratory demonstrated that E 2 increases ACE2 mRNA abundance in adipocytes (15).…”

mentioning

confidence: 60%

“…Ovariectomy of HF-fed female mice reduced adipose ACE2 expression and plasma ANG-(1-7) concentrations and converted female mice to an obesity-hypertension phenotype (15). These results suggest that sexual dimorphism of obesity-hypertension may be associated with ACE2-mediated regulation of the ANG II/ANG-(1-7) balance, and that adipose ACE2 may contribute significantly to regulation of the balance of these vasoactive peptides.17␤-Estradiol (E 2 ) has been reported to regulate ACE2 expression both in vitro and in vivo (15,20,21). Moreover, results from our laboratory demonstrated that E 2 increases ACE2 mRNA abundance in adipocytes (15).…”

mentioning

confidence: 94%

Administration of 17β-estradiol to ovariectomized obese female mice reverses obesity-hypertension through an ACE2-dependent mechanism

Wang

Shoemaker

Thatcher

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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nikouris F, English VL, Cassis LA. Administration of 17␤-estradiol to ovariectomized obese female mice reverses obesityhypertension through an ACE2-dependent mechanism. Am J Physiol Endocrinol Metab 308: E1066 -E1075, 2015. First published April 14, 2015 doi:10.1152/ajpendo.00030.2015-We recently demonstrated that female mice are resistant to the development of obesity-induced hypertension through a sex hormone-dependent mechanism that involved adipose angiotensin-converting enzyme 2 (ACE2). In this study, we hypothesized that provision of 17␤-estradiol (E2) to ovariectomized (OVX) high-fat (HF)-fed female hypertensive mice would reverse obesity-hypertension through an ACE2-dependent mechanism. Pilot studies defined dose-dependent effects of E2 in OVX female mice on serum E2 concentrations and uterine weights. An E2 dose of 36 g/ml restored normal serum E2 concentrations and uterine weights. Therefore, HF-fed OVX female Ace2and Ace2 Ϫ/Ϫ mice were administered vehicle or E2 (36 g/ml) for 16 wk. E2 administration significantly decreased body weights of HF-fed OVX female Ace2 ϩ/ϩ and Ace2 Ϫ/Ϫ mice of either genotype. At 15 wk, E2 administration decreased systolic blood pressure (SBP) of OVX HF-fed Ace2 ϩ/ϩ but not Ace2 Ϫ/Ϫ females during the light but not the dark cycle. E2-mediated reductions in SBP in Ace2 ϩ/ϩ females were associated with significant elevations in adipose ACE2 mRNA abundance and activity and reduced plasma ANG II concentrations. In contrast to females, E2 administration had no effect on any parameter quantified in HF-fed male hypertensive mice. In 3T3-L1 adipocytes, E2 promoted ACE2 mRNA abundance through effects at estrogen receptor-␣ (ER␣) and resulted in ER␣-mediated binding at the ACE2 promoter. These results demonstrate that E2 administration to OVX females reduces obesity-induced elevations in SBP (light cycle) through an ACE2-dependent mechanism. Beneficial effects of E2 to decrease blood pressure in OVX obese females may result from stimulation of adipose ACE2.17␤-estradiol; blood pressure; ovariectomy; renin-angiotensin system THE PREVALENCE OF HYPERTENSION has consistently risen in the United States largely due to the increasing prevalence of obesity. Data from the most recent National Health and Nutrition Examination Survey (NHANES) demonstrate that the prevalence of hypertension is rising at a faster rate in females than in males (6). It is generally well accepted, based on data from cross-sectional studies, that adult males are at a higher risk to develop hypertension than females until after menopause, when female prevalence of both obesity and hypertension increases markedly (27,28). Mechanisms for the role of menopause in the increasing prevalence of hypertension in females, or for the faster rise in hypertension prevalence in females compared with males are unclear.An activated renin-angiotensin system (RAS) has been suggested to contribute to the development of experimental and human obesity-induced hypertension (2,9,12,14). Indeed, recent studies from our laboratory demonstrate...

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Role of angiotensin‐converting enzyme 2 and angiotensin(1–7) in 17β‐oestradiol regulation of renal pathology in renal wrap hypertension in rats

Cited by 107 publications

References 45 publications

Protective regulation of the ACE2/ACE gene expression by estrogen in human atrial tissue from elderly men

Protective regulation of the ACE2/ACE gene expression by estrogen in human atrial tissue from elderly men

Estrogen regulation of the brain renin-angiotensin system in protection against angiotensin II-induced sensitization of hypertension

Administration of 17β-estradiol to ovariectomized obese female mice reverses obesity-hypertension through an ACE2-dependent mechanism

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