How Is the Brain Renin–Angiotensin System Regulated?

Nakagawa, Pablo; Sigmund, Curt D.

doi:10.1161/hypertensionaha.117.08550

Cited by 60 publications

(50 citation statements)

References 115 publications

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“…10 Increased sympathetic outflow in humans has been attributed to be the basis of the failure of antihypertensive therapy in some forms of resistant hypertension such as refractory hypertension. 20 Whether refractory hypertension or neurogenic hypertension in humans is due to increased activity of the brain RAS remains an unanswered question.…”

Section: Discussionmentioning

confidence: 99%

“…We have reviewed possible mechanisms by which this transcriptional regulatory circuit could be operating. 10 …”

Section: Discussionmentioning

confidence: 99%

“…9,10 This has been interpreted as evidence for an involvement of the brain RAS in hypertension. These data combined with the absence of significant blood pressure effects when the same blockers are injected into the brain of normal animals has been interpreted to mean that brain RAS activity is increased in hypertension.…”

Section: Introductionmentioning

confidence: 96%

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Selective Deletion of Renin-b in the Brain Alters Drinking and Metabolism

et al. 2017

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The brain specific isoform of renin (Ren-b), has been proposed as a negative regulator of the brain renin-angiotensin system (RAS). We analyzed mice with a selective deletion of Ren-b which preserved expression of the classical renin (Ren-a) isoform. We reported that Ren-bNull mice exhibited central RAS activation and hypertension through increased expression of Ren-a, but the dipsogenic and metabolic effects in Ren-bNull mice are unknown. Fluid intake was similar in control and Ren-bNull mice at baseline and both exhibited an equivalent dipsogenic response to DOCA-salt. Dehydration promoted increased water intake in Ren-bNull mice, particularly after DOCA-salt. Ren-bNull and control mice exhibited similar body weight when fed a chow diet. However, when fed a high fat diet, male Ren-bNull mice gained significantly less weight than control mice, an effect blunted in females. This difference was not due to changes in food intake, energy absorption or physical activity. Ren-bNull mice exhibited increased resting metabolic rate concomitant with increased uncoupled protein 1 expression and sympathetic nerve activity to the interscapular brown adipose tissue (BAT), suggesting increased thermogenesis. Ren-bNull mice were modestly intolerant to glucose and had normal insulin sensitivity. Another mouse model with markedly enhanced brain RAS activity (sRA mice) exhibited pronounced insulin sensitivity concomitant with increased BAT glucose uptake. Altogether, these data support the hypothesis that the brain RAS regulates energy homeostasis by controlling resting metabolic rate, and that Ren-b deficiency increases brain RAS activity. Thus, the relative level of expression of Ren-b and Ren-a may control activity of the brain RAS.

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Section: Discussionmentioning

confidence: 99%

“…We have reviewed possible mechanisms by which this transcriptional regulatory circuit could be operating. 10 …”

Section: Discussionmentioning

confidence: 99%

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Selective Deletion of Renin-b in the Brain Alters Drinking and Metabolism

et al. 2017

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“…Reduced urine flow and sodium excretion are observed in AngII-dependent hypertension via AT1R (Kuczeriszka, Kompanowska-Jezierska, Sadowski, Prieto, & Navar, 2018; Tamura et al, 2015; Zhuo et al, 2016). Activation of AT1R in brain areas that exert cardiovascular control plays an important role in controlling BP (Nakagawa & Sigmund, 2017). …”

Section: Angiotensin Type 1 Receptor and Blood Pressurementioning

confidence: 99%

Effect of novel GPCR ligands on blood pressure and vascular homeostasis

Jara

Singh

Ünal

et al. 2019

Methods in Cell Biology

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Maintenance of normal blood pressure under conditions of drug treatment is a measure of system-wide neuro-hormonal controls and electrolyte/fluid volume homeostasis in the body. With increased interest in designing and evaluating novel drugs that may functionally select or allosterically modulate specific GPCR signaling pathways, techniques that allow us to measure acute and long-term effects on blood pressure are very important. Therefore, this chapter describes techniques to measure acute and long-term impact of novel GPCR ligands on blood pressure regulation. We will use the angiotensin type 1 receptor, a powerful blood pressure regulating GPCR, in detailing the methodology. Normal blood pressure maintenance depends upon dynamic modulation of angiotensin type 1 receptor activity by the hormone peptide angiotensin II. Chronic activation of angiotensin type 1 receptor creates hypertension and related cardiovascular disease states which are treated with angiotensin type 1 receptor blockers (ARBs). Thus, a prototype for evaluation of blood pressure control under experimental evaluation of novel drugs.

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“…; Lee‐Kirsch et al . ; Nakagawa & Sigmund, ), and angiotensin‐like immunoreactivity is densely present in the hypothalamus of SHRs (Weyhenmeyer & Phillips, ). Although the presence of the brain RAS remains controversial (van Thiel et al .…”

Section: Introductionmentioning

confidence: 99%

Endogenous AT1 receptor–protein kinase C activity in the hypothalamus augments glutamatergic input and sympathetic outflow in hypertension

Chen

Pan

2019

The Journal of Physiology

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Key points The angiotensin AT1 receptor expression and protein kinase C (PKC)‐mediated NMDA receptor phosphorylation levels in the hypothalamus are increased in a rat genetic model of hypertension. Blocking AT1 receptors or PKC activity normalizes the increased pre‐ and postsynaptic NMDA receptor activity of hypothalamic presympathetic neurons in hypertensive animals. Inhibition of AT1 receptor–PKC activity in the hypothalamus reduces arterial blood pressure and sympathetic nerve discharges in hypertensive animals. AT1 receptors in the hypothalamus are endogenously activated to sustain NMDA receptor hyperactivity and elevated sympathetic outflow via PKC in hypertension. Abstract Increased synaptic N‐methyl‐d‐aspartate receptor (NMDAR) activity in the hypothalamic paraventricular nucleus (PVN) plays a major role in elevated sympathetic output in hypertension. Although exogenous angiotensin II (AngII) can increase NMDAR activity in the PVN, whether endogenous AT1 receptor–protein kinase C (PKC) activity mediates the augmented NMDAR activity of PVN presympathetic neurons in hypertension is unclear. Here we show that blocking AT1 receptors with losartan or inhibiting PKC with chelerythrine significantly decreased the frequency of NMDAR‐mediated miniature excitatory postsynaptic currents (mEPSCs) and the amplitude of puff NMDA currents of retrogradely labelled spinally projecting PVN neurons in spontaneously hypertensive rats (SHRs). Also, treatment with chelerythrine abrogated the potentiating effect of AngII on mEPSCs and puff NMDA currents of labelled PVN neurons in SHRs. In contrast, neither losartan nor chelerythrine had any effect on mEPSCs or puff NMDA currents in labelled PVN neurons in Wistar–Kyoto (WKY) rats. Furthermore, levels of AT1 receptor mRNA and PKC‐mediated NMDAR phosphorylation in the PVN were significantly higher in SHRs than in WKY rats. In addition, microinjection of losartan or chelerythrine into the PVN substantially reduced blood pressure and renal sympathetic nerve discharges in SHRs but not in WKY rats. Chelerythrine blocked sympathoexcitatory responses to AngII microinjected into the PVN. Our findings suggest that endogenous AT1 receptor–PKC activity is essential for presynaptic and postsynaptic NMDAR hyperactivity of PVN presympathetic neurons and for the augmented sympathetic outflow in hypertension. This information advances our mechanistic understanding of the interplay between angiotensinergic and glutamatergic excitatory inputs in hypertension.

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How Is the Brain Renin–Angiotensin System Regulated?

Cited by 60 publications

References 115 publications

Selective Deletion of Renin-b in the Brain Alters Drinking and Metabolism

Selective Deletion of Renin-b in the Brain Alters Drinking and Metabolism

Effect of novel GPCR ligands on blood pressure and vascular homeostasis

Endogenous AT1 receptor–protein kinase C activity in the hypothalamus augments glutamatergic input and sympathetic outflow in hypertension

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