The Renin-Angiotensin System in the Central Nervous System and Its Role in Blood Pressure Regulation

Nakagawa, Pablo; Gomez, Javier A.; Grobe, Justin L; Sigmund, Curt D.

doi:10.1007/s11906-019-1011-2

Cited by 75 publications

(62 citation statements)

References 118 publications

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“…In this context, PRR can initiate its own signaling pathway and induce its pro-oxidative effects ( Labandeira-Garcia et al, 2017 ). Although it was shown that there is a relationship between PRR and neural development ( Trepiccione et al, 2016 ), RAS-independent functions of PRR within the brain are not yet clear ( Nakagawa et al, 2020 ).…”

Section: Structure Of the Brain Renin–angiotensin Systemmentioning

confidence: 99%

Brain Renin–Angiotensin System at the Intersect of Physical and Cognitive Frailty

et al. 2020

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The renin-angiotensin system (RAS) was initially considered to be part of the endocrine system regulating water and electrolyte balance, systemic vascular resistance, blood pressure, and cardiovascular homeostasis. It was later discovered that intracrine and local forms of RAS exist in the brain apart from the endocrine RAS. This brainspecific RAS plays essential roles in brain homeostasis by acting mainly through four angiotensin receptor subtypes; AT 1 R, AT 2 R, MasR, and AT 4 R. These receptors have opposing effects; AT 1 R promotes vasoconstriction, proliferation, inflammation, and oxidative stress while AT 2 R and MasR counteract the effects of AT 1 R. AT 4 R is critical for dopamine and acetylcholine release and mediates learning and memory consolidation. Consequently, aging-associated dysregulation of the angiotensin receptor subtypes may lead to adverse clinical outcomes such as Alzheimer's disease and frailty via excessive oxidative stress, neuroinflammation, endothelial dysfunction, microglial polarization, and alterations in neurotransmitter secretion. In this article, we review the brain RAS from this standpoint. After discussing the functions of individual brain RAS components and their intracellular and intracranial locations, we focus on the relationships among brain RAS, aging, frailty, and specific neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and vascular cognitive impairment, through oxidative stress, neuroinflammation, and vascular dysfunction. Finally, we discuss the effects of RAS-modulating drugs on the brain RAS and their use in novel treatment approaches.

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Section: Structure Of the Brain Renin–angiotensin Systemmentioning

confidence: 99%

Brain Renin–Angiotensin System at the Intersect of Physical and Cognitive Frailty

et al. 2020

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“…Ang-II, in turn, elicits its downstream physiological effects predominantly via the AT 1 R. However other components of the RAS can counter-regulate the ACE-Ang-II-AT 1 R pathway such as ACE2, Ang-(1-7), Mas receptor (MasR), alamandine, and the Masrelated G proteincoupled receptor member D (MrgD) ( Santos et al, 2003 ; Santos et al, 2018 ; Arendse et al, 2019 ; Paz Ocaranza et al, 2020 ). All RAS components have been identified in both central (brain) ( De Kloet et al, 2016 ; De Kloet et al, 2017 ; Nakagawa et al, 2020 ) and periphery (kidney, blood vessels, heart, adrenal gland) ( Fyhrquist and Saijonmaa, 2008 ).…”

Section: Physiology Of Ras and Cytokines In Hypertensionmentioning

confidence: 99%

ADAM17-Mediated Shedding of Inflammatory Cytokines in Hypertension

2020

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The increase of Angiontesin-II (Ang-II), one of the key peptides of the renin-angiotensin system (RAS), and its binding to the Ang-II type 1 receptor (AT 1 R) during hypertension is a crucial mechanism leading to AD\AM17 activation. Among the reported membrane anchored proteins cleaved by ADAM17, immunological cytokines (TNF-a, IFN-g, TGF-b, IL-4, IL-10, IL-13, IL-6, FKN) are the major class of substrates, modulation of which triggers inflammation. The rise in ADAM17 levels has both central and peripheral implications in inflammation-mediated hypertension. This narrative review provides an overview of the role of ADAM17, with a special focus on its cellular regulation on neuronal and peripheral inflammation-mediated hypertension. Finally, it highlights the importance of ADAM17 with regards to the biology of inflammatory cytokines and their roles in hypertension.

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“…Following the elucidation of the components of the classic RAS, comparable elements were identified in many body organs including the brain. The so-called brain RAS is associated with neurons, astrocytes and microglia functions in a paracrine, autocrine, and even intracrine signaling role ( Huber et al, 2017 ; Jackson et al, 2018 ; Nakagawa et al, 2020 ). Many CNS nuclei (i.e., the LT, PVN, RVLM, NTS and AP) implicated in cardiovascular control and fluid balance are rich in AT1-R-positive cells and are often innervated by axons containing some components of the RAS ( Sumners et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Interactions of the Brain Renin-Angiotensin-System (RAS) and Inflammation in the Sensitization of Hypertension

2020

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Mounting evidence indicates that the renin-angiotensin (RAS) and immune systems interact with one another in the central nervous system (CNS) and that they are importantly involved in the pathogenesis of hypertension. Components comprising the classic RAS were first identified in the periphery, and subsequently, similar factors were found to be generated de novo in many different organs including the brain. There is humoral-neural coupling between the systemic and brain RASs, which is important for controlling sympathetic tone and the release of endocrine factors that collectively determine blood pressure (BP). Similar to the interactions between the systemic and brain RASs is the communication between the peripheral and brain immune systems. Systemic inflammation activates the brain’s immune response. Importantly, the RAS and inflammatory factors act synergistically in brain regions involved in the regulation of BP. This review presents evidence of how such interactions between the brain RAS and central immune mechanisms contribute to the pathogenesis of hypertension. Emphasis focuses on the role of these interactions to induce neuroplastic changes in a central neural network resulting in hypertensive response sensitization (HTRS). Neuroplasticity and HTRS can be induced by challenges (stressors) presented earlier in life such as a low-dose of angiotensin II or high fat diet (HFD) feeding in adults. Similarly, the offspring of mothers with gestational hypertension or of mothers ingesting a HFD during pregnancy are reprogrammed and manifest HTRS when exposed to new stressors as adults. Consideration of the actions and interactions of the brain RAS and inflammatory mediators in the context of the induction and expression of HTRS will provide insights into the etiology of high BP that may lead to new strategies for the prevention and treatment of hypertension.

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The Renin-Angiotensin System in the Central Nervous System and Its Role in Blood Pressure Regulation

Cited by 75 publications

References 118 publications

Brain Renin–Angiotensin System at the Intersect of Physical and Cognitive Frailty

Brain Renin–Angiotensin System at the Intersect of Physical and Cognitive Frailty

ADAM17-Mediated Shedding of Inflammatory Cytokines in Hypertension

Interactions of the Brain Renin-Angiotensin-System (RAS) and Inflammation in the Sensitization of Hypertension

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