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      Renal Sensory Activity Regulates the γ-Aminobutyric Acidergic Inputs to the Paraventricular Nucleus of the Hypothalamus in Goldblatt Hypertension

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          Abstract

          Renal sensory activity is centrally integrated within brain nuclei involved in the control of cardiovascular function, suggesting that renal afferents regulate basal and reflex sympathetic vasomotor activity. Evidence has shown that renal deafferentation (DAx) evokes a hypotensive and sympathoinhibitory effect in experimental models of cardiovascular diseases; however, the underlying mechanisms involved in this phenomenon need to be clarified, especially those related to central aspects. We aimed to investigate the role of renal afferents in the control of γ-aminobutyric acid (GABA)ergic inputs to the paraventricular nucleus (PVN) of the hypothalamus in renovascular hypertensive (2K1C) rats and their influence in the regulation of cardiovascular function. Hypertension was induced by clipping the left renal artery. After 4 weeks, renal DAx was performed by exposing the left renal nerve to a 33 mM capsaicin solution for 15 min. After 2 weeks of DAx, microinjection of muscimol into the PVN was performed in order to evaluate the influence of GABAergic activity in the PVN and its contribution to the control of renal sympathetic nerve activity (rSNA) and blood pressure (BP). Muscimol microinjected into the PVN triggered a higher drop in BP and rSNA in the 2K1C rats and renal DAx mitigated these responses. These results suggest that renal afferents are involved in the GABAergic changes found in the PVN of 2K1C rats. Although the functional significance of this phenomenon needs to be clarified, it is reasonable to speculate that GABAergic alterations occur to mitigate microglia activation-induced sympathoexcitation in the PVN of 2K1C rats.

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          Most cited references35

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          Brain microglial cytokines in neurogenic hypertension.

          Accumulating evidence indicates a key role of inflammation in hypertension and cardiovascular disorders. However, the role of inflammatory processes in neurogenic hypertension remains to be determined. Thus, our objective in the present study was to test the hypothesis that activation of microglial cells and the generation of proinflammatory cytokines in the paraventricular nucleus (PVN) contribute to neurogenic hypertension. Intracerebroventricular infusion of minocycline, an anti-inflammatory antibiotic, caused a significant attenuation of mean arterial pressure, cardiac hypertrophy, and plasma norepinephrine induced by chronic angiotensin II infusion. This was associated with decreases in the numbers of activated microglia and mRNAs for interleukin (IL) 1beta, IL-6, and tumor necrosis factor-alpha, and an increase in the mRNA for IL-10 in the PVN. Overexpression of IL-10 induced by recombinant adenoassociated virus-mediated gene transfer in the PVN mimicked the antihypertensive effects of minocycline. Furthermore, acute application of a proinflammatory cytokine, IL-1beta, into the left ventricle or the PVN in normal rats resulted in a significant increase in mean arterial pressure. Collectively, this indicates that angiotensin II induced hypertension involves activation of microglia and increases in proinflammatory cytokines in the PVN. These data have significant implications on the development of innovative therapeutic strategies for the control of neurogenic hypertension.
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            Sympathetic neural activity in hypertension and related diseases.

            Several hemodynamic variables, such as blood pressure, vascular resistance, cardiac output, and heart rate, are regulated, among others, by sympathetic cardiovascular influences. This has led many years ago investigators to advance the hypothesis that alterations in the sympathetic modulation of the cardiovascular system may occur in hypertension and related disease. The role of the sympathetic nervous system as promoter and amplifier of the hypertensive state has been examined in a consistent number of studies carried out by making use of sophisticated and sensitive approaches to evaluate adrenergic function, such as the norepinephrine spillover technique and the recording of efferent postganglionic muscle sympathetic-nerve traffic. The results of the above-mentioned investigations support the concept that adrenergic activation characterizes essential hypertension, correlating with the clinical severity of the disease. Furthermore, sympathetic cardiovascular influences may favor the hypertensive disease progression, by concurring with other hemodynamic and nonhemodynamic factors at the development of target organ damage. Finally, an adrenergic overdrive of pronounced degree also characterizes hypertension-related cardiovascular and metabolic disease. In several of these clinical conditions, the adrenergic overdrive plays a role in the disease's physiopathology and prognosis. The data reviewed in this article provide evidence that sympathetic activation represents a hallmark of the essential hypertensive state. They further show that adrenergic neural factors may participate at the development and progression of the hypertensive state and its complications. This represents the rationale for the use of antihypertensive and, in more in general, cardiovascular drugs capable to exert sympatho-inhibitory effects.
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              Astrocytes are GABAergic cells that modulate microglial activity.

              GABA is assumed to function in brain only as an inhibitory neurotransmitter. Here we report a much broader CNS role. We show that human astrocytes are GABAergic cells, and that human microglia are GABAceptive cells. We show that in adult human brain tissue, astrocytes immunostain for the GABA synthesizing enzyme GAD 67, the GABA metabolizing enzyme GABA-T and the GABA(A) and GABA(B) receptors. The intensity of staining is comparable or greater to that observed for known inhibitory neurons. We show that cultured human astrocytes strongly express the mRNA and protein for GAD 67, as well as GABA-T, and the GABA(A) and GABA(B) receptors. We further show that cultured human microglia express the mRNA and protein for GABA-T, in addition to the GABA(A) and GABA(B) receptors characterizing them as GABAceptive cells. We demonstrate that GABA suppresses the reactive response of both astrocytes and microglia to the inflammatory stimulants lipopolysaccharide (LPS) and interferon-γ by inhibiting induction of inflammatory pathways mediated by NFκB and P38 MAP kinase. This results in a reduced release of the inflammatory cytokines TNFα and IL-6 and an attenuation of conditioned medium neurotoxicity toward neuroblastoma SH-SY5Y cells. These inhibitory reactions are partially mimicked by the GABA(A) receptor agonist muscimol and the GABA(B) receptor agonist baclofen, indicating that GABA can stimulate both types of receptors in astrocytes as well as microglia. We conclude that the antiinflammatory actions of GABA offer new therapeutic opportunities since agonists should enhance the effectiveness of other antiinflammatory agents that operate through non-GABA pathways. © 2010 Wiley-Liss, Inc.
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                Author and article information

                Contributors
                Journal
                Front Physiol
                Front Physiol
                Front. Physiol.
                Frontiers in Physiology
                Frontiers Media S.A.
                1664-042X
                15 December 2020
                2020
                : 11
                : 601237
                Affiliations
                Department of Physiology, Cardiovascular Division, Escola Paulista de Medicina, Universidade Federal de São Paulo , São Paulo, Brazil
                Author notes

                Edited by: H Della Coletta Francescato, University of São Paulo, Brazil

                Reviewed by: Aline M. A. De Souza, Georgetown University, United States; Oscar Lorenzo, Universidad Autónoma Madrid, Spain

                *Correspondence: Erika E. Nishi, enishi@ 123456unifesp.br

                These authors have contributed equally to this work

                This article was submitted to Renal and Epithelial Physiology, a section of the journal Frontiers in Physiology

                Article
                10.3389/fphys.2020.601237
                7769809
                33384613
                d9c2244c-a778-4308-95e9-7dd49dbda21a
                Copyright © 2020 Milanez, Veiga, Martins, Pontes, Bergamaschi, Campos and Nishi.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 31 August 2020
                : 27 November 2020
                Page count
                Figures: 3, Tables: 1, Equations: 0, References: 35, Pages: 8, Words: 6194
                Funding
                Funded by: Coordenação de Aperfeiçoamento de Pessoal de Nível Superior 10.13039/501100002322
                Funded by: São Paulo Research Foundation (FAPESP
                Award ID: 18/02671-3
                Funded by: Brazilian National Research Council
                Award ID: 406233/2018-7
                Award ID: 0817/2018
                Award ID: 17/03905-5
                Award ID: 18/11909-3
                Award ID: 18/01898-4
                Categories
                Physiology
                Brief Research Report

                Anatomy & Physiology
                renal denervation,neuroinflammation,γ-aminobutyric acid,renovascular hypertension,afferent innervation

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