An Intracellular Renin-Angiotensin System in Neurons: Fact, Hypothesis, or Fantasy

Grobe, Justin L; Xu, Di; Sigmund, Curt D.

doi:10.1152/physiol.00002.2008

Cited by 156 publications

(156 citation statements)

References 54 publications

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“…The RAS exists in two forms: a circulatory form where ANG II acts as an endocrine factor, and a tissue-specific form, where local production of ANG II acts in an autocrine or paracrine manner to induce AT 1 R signaling on ANG II producing or nearby cells (75). Intracrine, or intracellular forms of the RAS, have also been described (46,109). Although the generation and action of other angiotensin peptides in the brain (such as ANG [1][2][3][4][5][6][7] by ACE2) has garnered considerable attention (147), this review will focus primarily on ANG II.…”

mentioning

confidence: 99%

Mechanisms of brain renin angiotensin system-induced drinking and blood pressure: importance of the subfornical organ

Coble¹,

Grobe

Johnson³

et al. 2015

American Journal of Physiology-Regulatory, Integrative and Comp

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Coble JP, Grobe JL, Johnson AK, Sigmund CD. Mechanisms of brain renin angiotensin system-induced drinking and blood pressure: importance of the subfornical organ. Am J Physiol Regul Integr Comp Physiol 308: R238 -R249, 2015. First published December 17, 2014 doi:10.1152/ajpregu.00486.2014.-It is critical for cells to maintain a homeostatic balance of water and electrolytes because disturbances can disrupt cellular function, which can lead to profound effects on the physiology of an organism. Dehydration can be classified as either intra-or extracellular, and different mechanisms have developed to restore homeostasis in response to each. Whereas the renin-angiotensin system (RAS) is important for restoring homeostasis after dehydration, the pathways mediating the responses to intra-and extracellular dehydration may differ. Thirst responses mediated through the angiotensin type 1 receptor (AT 1R) and angiotensin type 2 receptors (AT 2R) respond to extracellular dehydration and intracellular dehydration, respectively. Intracellular signaling factors, such as protein kinase C (PKC), reactive oxygen species (ROS), and the mitogen-activated protein (MAP) kinase pathway, mediate the effects of central angiotensin II (ANG II). Experimental evidence also demonstrates the importance of the subfornical organ (SFO) in mediating some of the fluid intake effects of central ANG II. The purpose of this review is to highlight the importance of the SFO in mediating fluid intake responses to dehydration and ANG II.angiotensin; blood pressure; barin; fluid; renin FLUID BALANCE is crucial for the homeostasis and survival of organisms because they have to properly maintain fluid and electrolyte concentrations for the normal function of all cells. Fluid balance can go awry in pathological states such as in chronic kidney disease and diabetes. Among its many roles in maintaining homeostasis, the renin-angiotensin system (RAS) is an important regulator of fluid balance. The RAS achieves this through the actions of its main effector peptide, angiotensin II (ANG II) through the ANG II type 1 (AT 1 R) and type 2 (AT 2 R) receptors. Activation of AT 1 R by blood-borne ANG II in target tissues causes increases in sodium and water retention, arginine vasopressin (AVP), and aldosterone release, vasoconstriction, increased sympathetic nervous system activity, and increased fluid intake. ANG II is produced by the consecutive enzymatic action of renin on its substrate angiotensinogen (AGT) and by angiotensin-converting enzyme (ACE) on its substrate angiotensin I (ANG I). The renin-AGT cleavage step is generally the rate-limiting step in the production of ANG II, and this is certainly true in the brain where the amount of renin is limiting. The RAS exists in two forms: a circulatory form where ANG II acts as an endocrine factor, and a tissue-specific form, where local production of ANG II acts in an autocrine or paracrine manner to induce AT 1 R signaling on ANG II producing or nearby cells (75). Intracrine, or intracellular forms of the RAS, hav...

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mentioning

confidence: 99%

Mechanisms of brain renin angiotensin system-induced drinking and blood pressure: importance of the subfornical organ

Coble¹,

Grobe

Johnson³

et al. 2015

American Journal of Physiology-Regulatory, Integrative and Comp

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“…For example, in rats exposed to CIH, peripheral administration of losartan, an angiotensin II (ANG II) type 1 receptor (AT1R) antagonist, has been shown to prevent the increase in MAP (14,16,18). ANG II is a major effector peptide of the RAS (21). Most of the physiological actions of ANG II are mediated thought its actions on AT1R (10,51).…”

mentioning

confidence: 99%

Angiotensin II type 1a receptors in subfornical organ contribute towards chronic intermittent hypoxia-associated sustained increase in mean arterial pressure

Saxena

Little

Nedungadi

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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Saxena A, Little JT, Nedungadi TP, Cunningham JT. Angiotensin II type 1a receptors in subfornical organ contribute towards chronic intermittent hypoxia-associated sustained increase in mean arterial pressure. Am J Physiol Heart Circ Physiol 308: H435-H446, 2015. First published December 24, 2014 doi:10.1152/ajpheart.00747.2014.-Sleep apnea is associated with hypertension. The mechanisms contributing to a sustained increase in mean arterial pressure (MAP) even during normoxic awake-state remain unknown. Rats exposed to chronic intermittent hypoxia for 7 days, a model of the hypoxemia associated with sleep apnea, exhibit sustained increases in MAP even during the normoxic dark phase. Activation of the renin-angiotensin system (RAS) has been implicated in chronic intermittent hypoxia (CIH) hypertension. Since the subfornical organ (SFO) serves as a primary target for the central actions of circulating ANG II, we tested the effects of ANG II type 1a receptor (AT1aR) knockdown in the SFO on the sustained increase in MAP in this CIH model. Adeno-associated virus carrying green fluorescent protein (GFP) and small-hairpin RNA against either AT1aR or a scrambled control sequence (SCM) was stereotaxically injected in the SFO of rats. After recovery, MAP, heart rate, respiratory rate, and activity were continuously recorded using radiotelemetry. In the normoxic groups, the recorded variables did not deviate from the baseline values. Both CIH groups exhibited significant increases in MAP during CIH exposures (P Ͻ 0.05). During the normoxic dark phase in the CIH groups, only the SCMinjected group exhibited a sustained increase in MAP (P Ͻ 0.05). The AT1aR-CIH group showed significant decreases in FosB/⌬FosB staining in the median preoptic nucleus and the paraventricular nuclei of the hypothalamus compared with the SCM-CIH group. Our data indicate that AT1aRs in the SFO are critical for the sustained elevation in MAP and increased FosB/⌬FosB expression in forebrain autonomic nuclei associated with CIH. angiotensin receptor; subfornical organ; chronic intermittent hypoxia; obstructive sleep apnea; AT1aR SLEEP APNEA (SA) is increasingly being recognized as a cause of neurogenic and treatment-resistant hypertension (12,19,32,37,52). SA is associated with a sustained increase in sympathetic nerve activity (SNA) and mean arterial pressure (MAP) even during periods of wakefulness and normoxia (4, 33). Animal models of chronic intermittent hypoxia (CIH), such as the one introduced by Fletcher at al. (17), produce cardiovascular sequelae similar to sleep apnea (11). Together, it appears that CIH episodes lead to pathophysiological adaptations that may generate and sustain a heightened basal MAP, which is partially dependent on increased SNA.The renin-angiotensin system (RAS) is activated during CIH (11,16,54), and it contributes to CIH hypertension (11, 16). For example, in rats exposed to CIH, peripheral administration of losartan, an angiotensin II (ANG II) type 1 receptor (AT1R) antagonist, has been shown to prevent the increase ...

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“…The immunocytochemical localization of angiotensinogen in the brain has indicate it is present in neurons of forbrain, thalamus, hypothalamus, brain stem, magnocellular neurons of the paraventricular nucleus, supraoptic nucleus, nucleus of the solitary tract, and circumventricular organs [21]. Recent data from Justin et al support the hypothesis that angiotensins may act as neurotransmitters and neuromodulators in the brain [22]. Angiotensinergic neurons in the circumventricular organs are connected with other regions in the brain linked to central blood pressure control and the regulation of body fluid homeostasis.…”

Section: Discussionmentioning

confidence: 94%

“…Furthermore, central injection of AT 1 receptor antagonist, Losartan, blocks AT 1 receptors and influences on central angiotensin mechanisms [24,26]. Infusion of Ang II into a lateral cerebral ventricle produce an increase in blood pressure [27,20,28], increase in mean arterial pressure [29,30], decrease in urine flow [27], regulate hydromineral balance [22], induce the pressor response [31], stimulate AVP and OT release [20,28] and elevate RSNA (renal sympathetic nerve activity) [32]. Losartan blocks water intake in intracellular and extracellular dehydrated conditions, inhibits the release of AVP and OT, reduces RSNA response and antidiuretic action [5,32].…”

Section: Discussionmentioning

confidence: 99%

Interaction between Dopaminergic and Angiotensinergic Systems on Thirst in Adult Male Rats

Sharifkhodaei¹,

Naghdi²,

Oryan³

2012

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Thirst, which provides the motivation to drink, is an important component of the coordinated sequence of physiological responses that maintain the volume and composition of body fluids. Special structures in the central nervous system like periventricular organs detect changes in these parameters continuously. The present study investigated the interaction between dopaminergic and angiotensinergic systems on water intake in adult male rats. Intracerebroventricular (ICV) injections were carried out in all experiments after 24 h deprivation of water intake. After the deprivation interval, the volume of consumed water was measured for 1 h. Administration the angiotensinergic (AT 1 ) receptor antagonist Losartan (45 µg/rat), and the dopaminergic antagonist Chlorpromazine (40 µg/rat) significantly decreased water intake when compared to saline-treated controls. In contrast, ICV microinjection of the dopaminergic agonist Bromocriptine (10 µg/rat) significantly increased water intake when compared to saline-treated controls. ICV injection of Bromocriptine 15 min after Losartan administration was able to attenuate the inhibitory effect of Losartan on water intake, whereas administration of Chlorpromazine 15 min after Losartan was unable to change the Losartan effect. These results suggest that the dopaminergic system interactions with the angiotensinergic system to regulate water intake through circumventricular organs. Dopaminergic and angiotensinergic neurons can monitor and regulate water intake via the stimulatory and inhibitory effects on each other, respectively.

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An Intracellular Renin-Angiotensin System in Neurons: Fact, Hypothesis, or Fantasy

Cited by 156 publications

References 54 publications

Mechanisms of brain renin angiotensin system-induced drinking and blood pressure: importance of the subfornical organ

Mechanisms of brain renin angiotensin system-induced drinking and blood pressure: importance of the subfornical organ

Angiotensin II type 1a receptors in subfornical organ contribute towards chronic intermittent hypoxia-associated sustained increase in mean arterial pressure

Interaction between Dopaminergic and Angiotensinergic Systems on Thirst in Adult Male Rats

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