Brain Angiotensin Type-1 and Type-2 Receptors in Physiological and Hypertensive Conditions: Focus on Neuroinflammation

Elsaafien, Khalid; Kloet, Annette D. de; Krause, Eric G.; Sumners, Colin

doi:10.1007/s11906-020-01062-0

Cited by 23 publications

(8 citation statements)

References 103 publications

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“…On the other hand, AM251 diminished the increase in BP induced by Ang II [ 55 ]. The pressor effects of Ang II and CP55940 given into the PVN result mainly from the activation of facilitatory AT 1 Rs on glutamatergic [ 73 , 74 ] and inhibitory CB 1 Rs on GABAergic [ 54 , 55 ] neurons, respectively ( Figure 5 ). In addition, Ang II may lead to the release of eCBs that, via CB 1 Rs, reduce the GABAergic tone and eventually lead to increased activity of the glutamatergic neurons associated with a pressor effect.…”

Section: Resultsmentioning

confidence: 99%

Cross-Talk between the (Endo)Cannabinoid and Renin-Angiotensin Systems: Basic Evidence and Potential Therapeutic Significance

Mińczuk

Baranowska-Kuczko

Krzyżewska

et al. 2022

IJMS

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This review is dedicated to the cross-talk between the (endo)cannabinoid and renin angiotensin systems (RAS). Activation of AT1 receptors (AT1Rs) by angiotensin II (Ang II) can release endocannabinoids that, by acting at cannabinoid CB1 receptors (CB1Rs), modify the response to AT1R stimulation. CB1R blockade may enhance AT1R-mediated responses (mainly vasoconstrictor effects) or reduce them (mainly central nervous system-mediated effects). The final effects depend on whether stimulation of CB1Rs and AT1Rs induces opposite or the same effects. Second, CB1R blockade may diminish AT1R levels. Third, phytocannabinoids modulate angiotensin-converting enzyme-2. Additional studies are required to clarify (1) the existence of a cross-talk between the protective axis of the RAS (Ang II—AT2 receptor system or angiotensin 1-7—Mas receptor system) with components of the endocannabinoid system, (2) the influence of Ang II on constituents of the endocannabinoid system and (3) the (patho)physiological significance of AT1R-CB1R heteromerization. As a therapeutic consequence, CB1R antagonists may influence effects elicited by the activation or blockade of the RAS; phytocannabinoids may be useful as adjuvant therapy against COVID-19; single drugs acting on the (endo)cannabinoid system (cannabidiol) and the RAS (telmisartan) may show pharmacokinetic interactions since they are substrates of the same metabolizing enzyme of the transport mechanism.

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Section: Resultsmentioning

confidence: 99%

Cross-Talk between the (Endo)Cannabinoid and Renin-Angiotensin Systems: Basic Evidence and Potential Therapeutic Significance

Mińczuk

Baranowska-Kuczko

Krzyżewska

et al. 2022

IJMS

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“…Indeed, angiotensin II has been demonstrated to modulate synaptic proteins levels in vitro ( Kurihara et al, 2008 ) and regulate neuronal firing rates ( Li et al, 2003 ; Li and Pan, 2005 ) and membrane ionic currents when assessed using electrophysiological analysis ( Sumners et al, 1996 ; Wang et al, 1997 ). In addition, blocking AT1 receptor signaling on neurons could have also lowered glial activation ( Elsaafien et al, 2020 ) which in turn reduces neuronal dysfunction. Alternatively, the beneficial effects of ARBs on behavior could be mediated through modulation of inflammatory processes related to AT1 receptor signaling in the periphery.…”

Section: Discussionmentioning

confidence: 99%

Systemic Candesartan Treatment Modulates Behavior, Synaptic Protein Levels, and Neuroinflammation in Female Mice That Express Human APOE4

et al. 2021

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Evidence suggests that angiotensin receptor blockers (ARBs) could be beneficial for Alzheimer’s disease (AD) patients independent of any effects on hypertension. However, studies in rodent models directly testing the activity of ARB treatment on behavior and AD-relevent pathology including neuroinflammation, Aβ levels, and cerebrovascular function, have produced mixed results. APOE4 is a major genetic risk factor for AD and has been linked to many of the same functions as those purported to be modulated by ARB treatment. Therefore, evaluating the effects of ARB treatment on behavior and AD-relevant pathology in mice that express human APOE4 could provide important information on whether to further develop ARBs for AD therapy. In this study, we treated female and male mice that express the human APOE4 gene in the absence (E4FAD−) or presence (E4FAD+) of high Aβ levels with the ARB prodrug candesartan cilexetil for a duration of 4 months. Compared to vehicle, candesartan treatment resulted in greater memory-relevant behavior and higher hippocampal presynaptic protein levels in female, but not male, E4FAD− and E4FAD+ mice. The beneficial effects of candesartan in female E4FAD− and E4FAD+ mice occurred in tandem with lower GFAP and Iba1 levels in the hippocampus, whereas there were no effects on markers of cerebrovascular function and Aβ levels. Collectively, these data imply that the effects of ARBs on AD-relevant pathology may be modulated in part by the interaction between APOE genotype and biological sex. Thus, the further development of ARBs could provide therapeutic options for targeting neuroinflammation in female APOE4 carriers.

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“…High densities of AT 1 receptors are found in the subfornical organ (SFO), the paraventricular nucleus (PVN), the area postrema (AP), the nucleus of the solitary tract (NTS), and the rostral ventrolateral medulla (RVLM) [ 87 ]. AT 1 receptors are almost exclusively localized in neurons rather than in microglia, or astrocytes in these cardiovascular control centers [ 88 ]. Furthermore, the AT 1 receptor appears to be predominantly expressed on glutamatergic neurons [ 89 ].…”

Section: The Functional At 1 /At 2 ...mentioning

confidence: 99%

The AT1/AT2 Receptor Equilibrium Is a Cornerstone of the Regulation of the Renin Angiotensin System beyond the Cardiovascular System

et al. 2023

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The AT1 receptor has mainly been associated with the pathological effects of the renin-angiotensin system (RAS) (e.g., hypertension, heart and kidney diseases), and constitutes a major therapeutic target. In contrast, the AT2 receptor is presented as the protective arm of this RAS, and its targeting via specific agonists is mainly used to counteract the effects of the AT1 receptor. The discovery of a local RAS has highlighted the importance of the balance between AT1/AT2 receptors at the tissue level. Disruption of this balance is suggested to be detrimental. The fine tuning of this balance is not limited to the regulation of the level of expression of these two receptors. Other mechanisms still largely unexplored, such as S-nitrosation of the AT1 receptor, homo- and heterodimerization, and the use of AT1 receptor-biased agonists, may significantly contribute to and/or interfere with the settings of this AT1/AT2 equilibrium. This review will detail, through several examples (the brain, wound healing, and the cellular cycle), the importance of the functional balance between AT1 and AT2 receptors, and how new molecular pharmacological approaches may act on its regulation to open up new therapeutic perspectives.

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Brain Angiotensin Type-1 and Type-2 Receptors in Physiological and Hypertensive Conditions: Focus on Neuroinflammation

Cited by 23 publications

References 103 publications

Cross-Talk between the (Endo)Cannabinoid and Renin-Angiotensin Systems: Basic Evidence and Potential Therapeutic Significance

Cross-Talk between the (Endo)Cannabinoid and Renin-Angiotensin Systems: Basic Evidence and Potential Therapeutic Significance

Systemic Candesartan Treatment Modulates Behavior, Synaptic Protein Levels, and Neuroinflammation in Female Mice That Express Human APOE4

The AT1/AT2 Receptor Equilibrium Is a Cornerstone of the Regulation of the Renin Angiotensin System beyond the Cardiovascular System

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