Wide distribution of immunoreactive renin in nerve cells of human brain.

Slater, Eve E.; Defendini, Richard; Zimmerman, Earl A.

doi:10.1073/pnas.77.9.5458

Cited by 74 publications

(42 citation statements)

References 16 publications

(8 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…All components of the RAS are localized in the brain, and renin has been previously reported in the hypothalamus and cerebellar cortex in the mouse and rat brain and in neurons in most areas of the human brain (1,6,7,11,16,27). Our results now show that (P)RR is also expressed widely in the adult mouse brain and at high levels in nuclei important for the regulation of blood pressure and body fluid homeostasis, such as the subfornical organ, the paraventricular nucleus, the area postrema, the nucleus tractus solitarii, the rostroventrolateral medulla, and the nucleus ambiguus.…”

Section: Discussionmentioning

confidence: 99%

A role of the (pro)renin receptor in neuronal cell differentiation

Contrepas

Walker²,

Koulakoff³

et al. 2009

American Journal of Physiology-Regulatory, Integrative and Comp

View full text Add to dashboard Cite

The (pro)renin receptor [(P)RR] plays a pivotal role in the renin-angiotensin system. Experimental models emphasize the role of (P)RR in organ damage associated with hypertension and diabetes. However, a mutation of the (P)RR gene, resulting in frame deletion of exon 4 [⌬4-(P)RR] is associated with X-linked mental retardation (XLMR) and epilepsy pointing to a novel role of (P)RR in brain development and cognitive function. We have studied (P)RR expression in mouse brain, as well as the effect of transfection of ⌬4-(P)RR on neuronal differentiation of rat neuroendocrine PC-12 cells induced by nerve growth factor (NGF). In situ hybridization showed a wide distribution of (P)RR, including in key regions involved in the regulation of blood pressure and body fluid homeostasis. In mouse neurons, the receptor is on the plasma membrane and in synaptic vesicles, and stimulation by renin provokes ERK1/2 phosphorylation. In PC-12 cells, (P)RR localized mainly in the Golgi and in endoplasmic reticulum and redistributed to neurite projections during NGF-induced differentiation. In contrast, ⌬4-(P)RR remained cytosolic and inhibited NGF-induced neuronal differentiation and ERK1/2 activation. Cotransfection of PC-12 cells with (P)RR and ⌬4-(P)RR cDNA resulted in altered localization of (P)RR and inhibited (P)RR redistribution to neurite projections upon NGF stimulation. Furthermore, (P)RR dimerized with itself and with ⌬4-(P)RR, suggesting that the XLMR and epilepsy phenotype resulted from a dominant-negative effect of ⌬4-(P)RR, which coexists with normal transcript in affected males. In conclusion, our results show that (P)RR is expressed in mouse brain and suggest that the XLMR and epilepsy phenotype might result from a dominant-negative effect of the ⌬4-(P)RR protein.brain (P)RR expression; functional (P)RR; X-linked mental retardation THE CLASSICAL RENIN-ANGIOTENSIN system (RAS) is an intravascular enzymatic cascade that generates ANG II, considered the biologically active peptide, and plays a major role in the control of blood pressure, as well as fluid and salt balance. A receptor for renin and its proenzyme form, prorenin, called (pro)renin receptor [(P)RR] was recently cloned (20). The binding of renin and of prorenin results in increased angiotensin generation at the cell surface. Activation of (P)RR results in the activation of the MAP kinases ERK1/2 pathway and in upregulation of profibrotic genes, independently of ANG II generation (9, 10, 13, 21). These biochemical characteristics have generated a special interest in potential nonhemodynamic functions of renin ad prorenin. The receptor is abundantly expressed in adult human (20) and rat (14) organs, including the brain. Although overexpression of (P)RR is associated with a renal (15) and cardiovascular phenotype (3), it is surprising that alterations in the (P)RR gene, ATP6ap2 point to an essential role of (P)RR in cell survival and development of the central nervous system. In zebra fish, (P)RR/ATP6AP2 is expressed at a very early stage of development (www.zfin.o...

show abstract

Section: Discussionmentioning

confidence: 99%

A role of the (pro)renin receptor in neuronal cell differentiation

Contrepas

Walker²,

Koulakoff³

et al. 2009

American Journal of Physiology-Regulatory, Integrative and Comp

View full text Add to dashboard Cite

show abstract

“…Substantial controversy still remains as to the localization of renin-containing cells in the brain. For example, immunoreactive renin was detected in most nerve cells throughout the human brain, whereas it was detected only in hypothalamus and cerebellar cortex in the brain of rodents (17,18). We recently examined the cellular localization of renin in the brain of transgenic mice containing the hREN gene encoded on a large P1 artificial chromosome.…”

Section: Discussionmentioning

confidence: 99%

“…Later, immunoreactive renin was found in the hypothalamus and cerebellar cortex in the mouse and rat brain and in neurons in all areas of the human brain (17,18). Despite these observations and the clear documentation of the expression of the other RAS genes in the brain, the notion that renin is endogenously expressed in brain remains controversial.…”

mentioning

confidence: 92%

Glia- and Neuron-specific Expression of the Renin-Angiotensin System in Brain Alters Blood Pressure, Water Intake, and Salt Preference

Morimoto

Cassell

Sigmund

2002

Journal of Biological Chemistry

107

124

View full text Add to dashboard Cite

The purpose of this study is to examine the regulation of blood pressure and fluid and electrolyte homeostasis in mice overexpressing angiotensin II (Ang-II) in the brain and to determine whether there are significant physiologic differences in Ang-II production in neurons or glia. Therefore, we generated and characterized transgenic mice overexpressing human renin (hREN) under the control of the glial fibrillary acidic protein (GFAP) promoter (GFAP-hREN) and synapsin-I promoter (SYN-hREN) and bred them with mice expressing human angiotensinogen (hAGT) under the control of the same promoters (GFAP-hAGT and SYN-hAGT). Both GFAP-hREN and SYN-hREN mice exhibited the highest hREN mRNA expression in the brain and had undetectable levels of hREN protein in the systemic circulation. In the brain of GFAP-hREN and SYN-hREN mice, hREN protein was observed almost exclusively in astrocytes and neurons, respectively. Transgenic mice overexpressing both hREN and hAGT transgenes in either glia or neurons were moderately hypertensive. In the gliatargeted mice, blood pressure could be corrected by intracerebroventricular injection of the Ang-II type 1 receptor antagonist losartan, and intravenous injection of a ganglion blocking agent, but not an arginine vasopressin V1 receptor antagonist, lowered blood pressure. These data suggest that stimulation of Ang-II type 1 receptors in the brain by Ang-II derived from local synthesis of renin and angiotensinogen can cause an elevation in blood pressure via a mechanism involving enhanced sympathetic outflow. Glia-and neuron-targeted mice also exhibited an increase in drinking volume and salt preference, suggesting that chronic overexpression of renin and angiotensinogen locally in the brain can result in hypertension and alterations in fluid homeostasis. The peptide angiotensin II (Ang-II)1 is the main circulating effector hormone of the renin-angiotensin system (RAS) and is able to act not only on peripheral vascular structures but also on the central nervous system (CNS) to increase blood pressure (BP) (1). Substantial evidence has accumulated that Ang-II has actions on the CNS including increasing sympathetic outflow, arginine vasopressin (AVP) release, water intake, and salt appetite (2). Existence of a local RAS in the CNS has been suggested, since all components of this system have been reported in the brain. In addition, several lines of evidence point to a contribution of an overactive brain RAS to the hypertensive state in spontaneously hypertensive rats, deoxycorticosterone acetate (DOCA) salt hypertensive rats, Dahl salt sensitive rats, and renal hypertensive rats (3-6).Despite numerous studies demonstrating the important cardiovascular effects of Ang-II or Ang-II receptor antagonists injected into the brain, it remains unclear whether RAS components synthesized in the brain, in particular renin and angiotensinogen (AGT), have an important role in the local synthesis of Ang-II. In the brain, AGT expression is localized mainly in astrocytes (glia) (7,8). To determine whether l...

show abstract

“…AGT exhibits a widespread distribution in astroglia throughout the brain but a much more selective regional distribution in neurons (7)(8)(9). Renin was previously identified in neurons (10,11), and using a renin promoter-directed enhanced GFP (EGFP) gene, we reported that renin-expressing cells are located in or near regions controlling cardiovascular function and are primarily neurons (12,13). Ang II, like other neurotransmitters, has been localized in neuronal processes and in the vicinity of nerve terminals (14).…”

Section: Introductionmentioning

confidence: 94%

Local production of angiotensin II in the subfornical organ causes elevated drinking

Sakai¹,

Agassandian²,

Morimoto³

et al. 2007

J. Clin. Invest.

142

139

View full text Add to dashboard Cite

. We generated double-transgenic mice expressing human renin (hREN) from a neuron-specific promoter and human AGT (hAGT) from its own promoter (SRA mice) to emulate this expression. SRA mice exhibited an increase in water and salt intake and urinary volume, which were significantly reduced after chronic intracerebroventricular delivery of losartan. Ang II-like immunoreactivity was markedly increased in the subfornical organ (SFO). To further evaluate the physiological importance of de novo Ang II production specifically in the SFO, we utilized a transgenic mouse model expressing a floxed version of hAGT (hAGT flox ), so that deletions could be induced with Cre recombinase. We targeted SFO-specific ablation of hAGT flox by microinjection of an adenovirus encoding Cre recombinase (AdCre). SRA flox mice exhibited a marked increase in drinking at baseline and a significant decrease in water intake after administration of AdCre/adenovirus encoding enhanced GFP (AdCre/AdEGFP), but not after administration of AdEGFP alone. This decrease only occurred when Cre recombinase correctly targeted the SFO and correlated with a loss of hAGT and angiotensin peptide immunostaining in the SFO. These data provide strong genetic evidence implicating de novo synthesis of Ang II in the SFO as an integral player in fluid homeostasis.

show abstract

Wide distribution of immunoreactive renin in nerve cells of human brain.

Cited by 74 publications

References 16 publications

A role of the (pro)renin receptor in neuronal cell differentiation

A role of the (pro)renin receptor in neuronal cell differentiation

Glia- and Neuron-specific Expression of the Renin-Angiotensin System in Brain Alters Blood Pressure, Water Intake, and Salt Preference

Local production of angiotensin II in the subfornical organ causes elevated drinking

Contact Info

Product

Resources

About