Evidence Supporting a Functional Role for Intracellular Renin in the Brain

Lavoie, Julie L.; Liu, Xuebo; Bianco, Robert A.; Beltz, Terry G.; Johnson, Alan Kim; Sigmund, Curt D.

doi:10.1161/01.hyp.0000203308.52919.dc

Cited by 74 publications

(77 citation statements)

References 42 publications

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“…[14][15][16][17][18][19] The potential role of intracellular Ang II could be traced back to an early study in which radiolabelled Ang II was found in the nuclei of vascular smooth muscle and cardiac cells following systemic administration. 20 However, Re [25][26][27] Haller et al showed that microinjection of Ang II directly into rat vascular smooth muscle cells increased intracellular calcium, which could be blocked by intracellular AT 1 -receptor blockers.…”

Section: Introductionmentioning

confidence: 99%

Review: Novel roles of intracrine angiotensin II and signalling mechanisms in kidney cells

Zhuo

2007

J Renin Angiotensin Aldosterone Syst

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Angiotensin II (Ang II) has powerful sodiumretaining, growth-promoting and proinflammatory properties in addition to its physiological role in maintaining body salt and fluid balance and blood pressure homeostasis. Increased circulating and local tissue Ang II is one of the most important factors contributing to the development of sodium and fluid retention, hypertension and target organ damage.The importance of Ang II in the pathogenesis of hypertension and target organ injury is best demonstrated by the effectiveness of angiotensinconverting enzyme (ACE) inhibitors and AT 1 -receptor antagonists in treating hypertension and progressive renal disease including diabetic nephropathy.The detrimental effects of Ang II are mediated primarily by the AT 1 -receptor, while the AT 2 -receptor may oppose the AT 1 -receptor. The classical view of the AT 1 -receptor-mediated effects of Ang II is that the agonist binds its receptors at the cell surface, and following receptor phosphorylation, activates downstream signal transduction pathways and intracellular responses. However, evidence is emerging that binding of Ang II to its cell surface AT 1 -receptors also activates endocytotic (or internalisation) processes that promote trafficking of both the effector and the receptor into intracellular compartments.Whether internalised Ang II has important intracrine and signalling actions is not well understood.The purpose of this article is to review recent advances in Ang II research with focus on the mechanisms underlying high levels of intracellular Ang II in proximal tubule cells and the contribution of receptor-mediated endocytosis of extracellular Ang II. Further attention is devoted to the question whether intracellular and/or internalised Ang II plays a physiological role by activating cytoplasmic or nuclear receptors in proximal tubule cells.This information may aid future development of drugs to prevent and treat Ang II-induced target organ injury in cardiovascular and renal diseases by blocking intracellular and/or nuclear actions of Ang II.

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Section: Introductionmentioning

confidence: 99%

Review: Novel roles of intracrine angiotensin II and signalling mechanisms in kidney cells

Zhuo

2007

J Renin Angiotensin Aldosterone Syst

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“…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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“…7 Since there was no information on regional distribution of expression of the human renin, different patterns for expression of intracellular versus secreted human renin may be responsible. Additionally, with intracellular human renin overexpression there was an increase in circulating mouse renin.…”

mentioning

confidence: 99%

“…An important issue raised by the Lavoie et al 7 article is relevant to glial versus neuronal origins of components of the brain RAS. Whether there are distinct actions of angiotensin peptides derived from either source remains an interesting area of active investigation.…”

mentioning

confidence: 99%

“…Whether there are distinct actions of angiotensin peptides derived from either source remains an interesting area of active investigation. The data from Lavoie et al 7 are interpreted that peptides derived from components of glial origin promote hypertension and polydipsia. Indeed, previous work shows that glial overexpression of human angiotensinogen and human renin in a double transgenic mouse leads to impairment in baroreflex sensitivity and an increase in resting blood pressure.…”

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confidence: 99%

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Approaches to Establishing Angiotensin II as a Neurotransmitter Revisited

Diz¹

2006

Hypertension

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D uring the past 3 to 4 decades, there has been debate on the presence as well as the role of local tissue renin-angiotensin systems (RAS) in cardiovascular physiology and pathophysiology. Although it is now accepted that all components of the RAS are present in a variety of extrarenal tissues and their regulation may be independent of the circulating hormonal system, the factors contributing to this regulation are still not well understood. Also apparent is that our understanding of the relationships among various cell types expressing individual RAS components and production of specific angiotensin peptides in each tissue is still lacking. This is particularly true of the brain RAS, where even after 20 years the question of whether there are angiotensinergic versus reninergic neurons or a complete functioning RAS in cerebrospinal fluid (CSF) or extracellular fluid or glia remains in question. 1 Ever since early reports provided biochemical evidence of RAS components in brain, controversy regarding their cellular localization, independence from the circulating system, and authenticity of the proteins and peptides persists. It is well accepted that angiotensinogen is present in CSF/interstitial fluid and localization via immunocytochemistry and in situ hybridization histochemistry reveals that production of the precursor protein is primarily in glia, but also in neurons, within key cardiovascular nuclei. Lingering questions remain concerning local expression of authentic renin in tissues, especially given that prorenin or active renin can be sequestered from the circulation 2 and other enzymes can exhibit similar proteolytic profiles under certain conditions. However, there is unequivocal evidence of discrete cells within the pituitary, choroid plexus, medulla oblongata, and hypothalamus that are positive for renin immunoreactivity colocalizing mainly with neurons, but in the medulla oblongata and subfornical organ, in glial elements as well. Evidence of renin mRNA in brain tissue provides a mechanism for local synthesis of the protein. Using green fluorescent protein driven by the renin promoter, 3 studies revealed predominant but not exclusive presence of renin mRNA in neurons. All enzymes required for subsequent processing of angiotensin I into active peptides, including converting enzyme (ACE) for angiotensin II, ACE2 and neprilysin for angiotensin-(1-7), and aminopetidases for angiotensins III and IV, are present on the basis of immunocytochemical or molecular approaches. The predominant localization of these secondary enzymes on plasma membranes is interpreted as evidence for extracellular formation of the final bioactive peptide products.Finally, evidence of receptors defined by molecular, functional, or binding methods for angiotensins II, III, IV, and (1-7) complete the brain RAS. The receptors are widely distributed throughout cardiovascular and neuroendocrine control centers as well as in areas of the brain more typically considered as part of motor and sensory processing and memory and affective beha...

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Evidence Supporting a Functional Role for Intracellular Renin in the Brain

Cited by 74 publications

References 42 publications

Review: Novel roles of intracrine angiotensin II and signalling mechanisms in kidney cells

Review: Novel roles of intracrine angiotensin II and signalling mechanisms in kidney cells

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

Approaches to Establishing Angiotensin II as a Neurotransmitter Revisited

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