Central angiotensinergic mechanisms associated with hypertension

O’Callaghan, Erin L.; Choong, Yan-Ting; Jancovski, Nikola; Allen, Andrew M.

doi:10.1016/j.autneu.2013.01.010

Cited by 22 publications

(30 citation statements)

References 127 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our data suggest that ACE2 activity in the SFO and PVN is important; however, knockdown of ACE2 in one of these regions of SL mice is not a limiting factor for the beneficial effect on BP. This could be because of the angiotensinergic projections between neurons in different regions (15,17). For example, in SFO AAV-Creinfected SL mice, although hACE2 was knocked down from this region, the PVN still overexpress ACE2 and therefore could inhibit the deleterious effects of ANG II originating from the SFO and promote inhibition of oxidative stress and inflammation.…”

Section: Discussionmentioning

confidence: 99%

“…It has been well established that the brain RAS plays critical roles in the central regulation of BP and in the pathogenesis of neurogenic hypertension (17). Many brain regions are involved in this process.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, these connections enable the PVN to indirectly or directly influence sympathetic nerve activity. All of the components of the RAS have been found in the PVN, including ANG II, AT 1 R, and ACE (17). ANG II excites neurons in the PVN to increase sympathetic activity (5), thus increasing BP.…”

Section: Discussionmentioning

confidence: 99%

“…An overactivated brain RAS leads to the development of neurogenic hypertension at least in part by increasing sympathetic outflow, blunting the baroreflex sensitivity and stimulating vasopressin secretion (17). Angiotensin-converting enzyme type 2 (ACE2), a pivotal RAS component, has been found in many regions in the bran, including SFO and PVN (8).…”

mentioning

confidence: 99%

“…THE BRAIN RENIN-ANGIOTENSIN system (RAS) plays a critical role in the regulation of blood pressure (BP) via its actions in various brain regions, such as subfornical organ (SFO), paraventricular nucleus (PVN), rostral ventrolateral medulla (RVLM), and nucleus tractus solitarius (NTS) (17). An overactivated brain RAS leads to the development of neurogenic hypertension at least in part by increasing sympathetic outflow, blunting the baroreflex sensitivity and stimulating vasopressin secretion (17).…”

mentioning

confidence: 99%

See 4 more Smart Citations

Brain ACE2 overexpression reduces DOCA-salt hypertension independently of endoplasmic reticulum stress

Xia

Queiroz

Sriramula

et al. 2015

American Journal of Physiology-Regulatory, Integrative and Comp

View full text Add to dashboard Cite

-Endoplasmic reticulum (ER) stress was previously reported to contribute to neurogenic hypertension while neuronal angiotensin-converting enzyme type 2 (ACE2) overexpression blunts the disease. To assess which brain regions are important for ACE2 beneficial effects and the contribution of ER stress to neurogenic hypertension, we first used transgenic mice harboring a floxed neuronal hACE2 transgene (SL) and tested the impact of hACE2 knockdown in the subfornical organ (SFO) and paraventricular nucleus (PVN) on deoxycorticosterone acetate (DOCA)-salt hypertension. SL and nontransgenic (NT) mice underwent DOCA-salt or sham treatment while infected with an adenoassociated virus (AAV) encoding Cre recombinase (AAV-Cre) or a control virus (AAV-green fluorescent protein) to the SFO or PVN. DOCA-salt-induced hypertension was reduced in SL mice, with hACE2 overexpression in the brain. This reduction was only partially blunted by knockdown of hACE2 in the SFO or PVN, suggesting that both regions are involved but not essential for ACE2 regulation of blood pressure (BP). DOCA-salt treatment did not increase the protein levels of ER stress and autophagy markers in NT mice, despite a significant increase in BP. In addition, these markers were not affected by hACE2 overexpression in the brain, despite a significant reduction of hypertension in SL mice. To further assess the role of ER stress in neurogenic hypertension, NT mice were infused intracerebroventricularlly with tauroursodeoxycholic acid (TUDCA), an ER stress inhibitor, during DOCA-salt treatment. However, TUDCA infusion failed to blunt the development of hypertension in NT mice. Our data suggest that brain ER stress does not contribute to DOCA-salt hypertension and that ACE2 blunts neurogenic hypertension independently of ER stress. neurogenic hypertension; central nervous system; blood pressure; angiotensin-converting enzyme type 2; deoxycorticosterone acetate THE BRAIN RENIN-ANGIOTENSIN system (RAS) plays a critical role in the regulation of blood pressure (BP) via its actions in various brain regions, such as subfornical organ (SFO), paraventricular nucleus (PVN), rostral ventrolateral medulla (RVLM), and nucleus tractus solitarius (NTS) (17). An overactivated brain RAS leads to the development of neurogenic hypertension at least in part by increasing sympathetic outflow, blunting the baroreflex sensitivity and stimulating vasopressin secretion (17). Angiotensin-converting enzyme type 2 (ACE2), a pivotal RAS component, has been found in many regions in the bran, including SFO and PVN (8). Numerous studies have shown that ACE2 has opposite properties to that of the classic RAS via its conversion of angiotensin (ANG) II into ANG-(1-7) (20). We previously reported that overexpression of ACE2 in the brain blunts the development of hypertension in several animal models (9, 31). However, it is not clear which brain regions might be more important for the preservation of ACE2 compensatory activity.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Brain ACE2 overexpression reduces DOCA-salt hypertension independently of endoplasmic reticulum stress

Xia

Queiroz

Sriramula

et al. 2015

American Journal of Physiology-Regulatory, Integrative and Comp

View full text Add to dashboard Cite

show abstract

Small‐molecule AT2 receptor agonists

Hallberg

Sumners

Steckelings

et al. 2017

Medicinal Research Reviews

View full text Add to dashboard Cite

The discovery of the first selective, small-molecule ATR receptor (AT2R) agonist compound 21 (C21) (8) that is now extensively studied in a large variety of in vitro and in vivo models is described. The sulfonylcarbamate derivative 8, encompassing a phenylthiofen scaffold is the drug-like agonist with the highest affinity for the AT2R reported to date (K = 0.4 nM). Structure-activity relationships (SAR), regarding different biaryl scaffolds and functional groups attached to these scaffolds and with a particular focus on the impact of various para substituents displacing the methylene imidazole group of 8, are discussed. Furthermore, the consequences of migration of the methylene imidazole group and presumed structural requirements for ligands that are aimed as AT2R agonists (e.g. 8) or AT2R antagonists (e.g. 9), respectively, are briefly addressed. A summary of the pharmacological actions of C21 (8) is also presented.

show abstract

Female protection from slow‐pressor effects of angiotensin II involves prevention of ROS production independent of NMDA receptor trafficking in hypothalamic neurons expressing angiotensin 1A receptors

Marques-Lopes

Lynch

Kempen

et al. 2015

Synapse

View full text Add to dashboard Cite

Renin-angiotensin system over-activity, up-regulation of post-synaptic NMDA receptor function, and increased reactive oxygen species (ROS) production in the hypothalamic paraventricular nucleus (PVN) are hallmarks of angiotensin II (AngII)-induced hypertension, which is far more common in young males than in young females. We hypothesize that the sex differences in hypertension are related to differential AngII-induced changes in post-synaptic trafficking of the essential NMDA receptor GluN1 subunit and ROS production in PVN cells expressing angiotensin type 1a receptor (AT1aR). We tested this hypothesis using slow-pressor (14 day) infusion of AngII (600ng/kg/min) in mice, which elicits hypertension in males but not in young females. Two month-old male and female transgenic mice expressing enhanced green fluorescent protein (EGFP) in AT1aR-containing cells were used. In males, but not females, AngII increased blood pressure and ROS production in AT1aR-EGFP PVN cells at baseline and following NMDA treatment. Electron microscopy showed that AngII increased cytoplasmic and total GluN1-silver-intensified immunogold (SIG) densities, and induced a trend towards an increase in near plasmalemmal GluN1-SIG density in AT1aR-EGFP dendrites of males and females. Moreover, AngII decreased dendritic area and diameter in males, but increased dendritic area of small (<1μm) dendrites and decreased diameter of large (>1μm) dendrites in females. Fluorescence microscopy revealed that AT1aR and estrogen receptor β do not co-localize suggesting that, if estrogen is involved, its effect is indirect. The data suggest that the sexual dimorphism in AngII-induced hypertension is associated with sex differences in ROS production in AT1aR-containing PVN cells, but not with post-synaptic NMDA receptor trafficking.

show abstract

Central angiotensinergic mechanisms associated with hypertension

Cited by 22 publications

References 127 publications

Brain ACE2 overexpression reduces DOCA-salt hypertension independently of endoplasmic reticulum stress

Brain ACE2 overexpression reduces DOCA-salt hypertension independently of endoplasmic reticulum stress

Small‐molecule AT2 receptor agonists

Female protection from slow‐pressor effects of angiotensin II involves prevention of ROS production independent of NMDA receptor trafficking in hypothalamic neurons expressing angiotensin 1A receptors

Contact Info

Product

Resources

About