scholarly journals Increased (pro)renin receptor expression in the subfornical organ of hypertensive humans

2018 ◽  
Vol 314 (4) ◽  
pp. H796-H804 ◽  
Author(s):  
Silvana G. Cooper ◽  
Darshan P. Trivedi ◽  
Rieko Yamamoto ◽  
Caleb J. Worker ◽  
Cheng-Yuan Feng ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Animal Models ◽  
Systolic Blood Pressure ◽  
Renin Angiotensin System ◽  
Subfornical Organ ◽  
Antihypertensive Drug Therapy ◽  
Angiotensin System ◽  
Human Hypertension ◽  
Renin Angiotensin ◽  
The Brain

The central nervous system plays an important role in essential hypertension in humans and in animal models of hypertension through modulation of sympathetic activity and Na+ and body fluid homeostasis. Data from animal models of hypertension suggest that the renin-angiotensin system in the subfornical organ (SFO) of the brain is critical for hypertension development. We recently reported that the brain (pro)renin receptor (PRR) is a novel component of the brain renin-angiotensin system and could be a key initiator of the pathogenesis of hypertension. Here, we examined the expression level and cellular distribution of PRR in the SFO of postmortem human brains to assess its association with the pathogenesis of human hypertension. Postmortem SFO tissues were collected from hypertensive and normotensive human subjects. Immunolabeling for the PRR and a retrospective analysis of clinical data were performed. We found that human PRR was prominently expressed in most neurons and microglia, but not in astrocytes, in the SFO. Importantly, PRR levels in the SFO were elevated in hypertensive subjects. Moreover, PRR immunoreactivity was significantly correlated with systolic blood pressure but not body weight, age, or diastolic blood pressure. Interestingly, this correlation was independent of antihypertensive drug therapy. Our data indicate that PRR in the SFO may be a key molecular player in the pathogenesis of human hypertension and, as such, could be an important focus of efforts to understand the neurogenic origin of hypertension. NEW & NOTEWORTHY This study provides evidence that, in the subfornical organ of the human brain, the (pro)renin receptor is expressed in neurons and microglia cells but not in astrocytes. More importantly, (pro)renin receptor immunoreactivity in the subfornical organ is increased in hypertensive humans and is significantly correlated with systolic blood pressure.

Abstract P061: Selective Deletion of Intracellular Renin in the Brain Causes Hypertension and Elevated Sympathetic Nervous System Activity

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Keisuke Shinohara ◽  
Benjamin J Weidemann ◽  
Matthew D Folchert ◽  
Xuebo Liu ◽  
Donald A Morgan ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Metabolic Rate ◽  
Systolic Blood Pressure ◽  
Neural Circuit ◽  
Resting Metabolic Rate ◽  
Renin Angiotensin System ◽  
Power Spectral Analysis ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
The Brain

Renin expression is regulated by two distinct promoter-1st exon combinations that target renin either for secretion (exon 1a for secreted renin) or cytoplasmic retention (exon 1b for intracellular renin, icREN). We developed icREN knockout (KO) mice by selectively deleting exon 1b. icREN KO mice are essentially brain-specific knockouts of icREN because icREN is predominantly expressed in the brain. Notably, systolic blood pressure measured by telemetry was increased in icREN KO mice (130±2 mmHg, n=8 vs 122±2 mmHg in controls, n=7, P<0.01). The low- to high-frequency ratio (LF/HF) derived from power spectral analysis of heart rate variability, a parameter of sympathetic nerve activity (SNA), was increased in icREN KO mice (KO: 1.24±0.21, n=7 vs control: 0.70±0.11, n=7, P<0.05). Body weight (BW) was normal in icREN KO mice compared to controls, but the BW gain and fat accumulation induced by high fat diet (HFD) were attenuated in male icREN KO mice (BW at 16 wks of HFD- KO: 36.8±1.2 g, n=8 vs control: 41.9±1.4 g, n=9; relative fat mass at 14 wks of HFD- KO: 27.7±1.7%, n=8 vs control: 34.4±2.3%, n=9, both P<0.05). The resting metabolic rate measured by respirometry was increased in icREN KO mice (0.156±0.005 kcal/h, n=46, P<0.05) vs controls (0.145±0.003 kcal/h, n=53), whereas food consumption and absorbed calories were not different. We previously reported that the brain renin-angiotensin system facilitates renal SNA (RSNA) response to acute intracerebroventricular (ICV) injection of leptin. Interestingly, the RSNA response to ICV leptin was greater in icREN KO mice (KO: 214±40 % baseline, n=5 vs control: 114±18 % baseline, n=10, P<0.01). AT1a receptor mRNA was upregulated in the paraventricular nucleus of icREN KO mice (P<0.05). Chronic ICV injection of losartan not only abolished the elevated blood pressure in icREN KO mice, but reduced it to below baseline in controls (systolic blood pressure, 111±3 mmHg in KO, n=5; 124±4 mmHg in controls, n=6). These data suggest that icREN deletion increases the activity of brain renin-angiotensin system and elevates blood pressure and metabolic rate through sympathetic activation. We conclude that this novel icREN isoform contributes to cardiovascular and metabolic control possibly as part of an inhibitory neural circuit.

scholarly journals Divergent mechanism regulating fluid intake and metabolism by the brain renin-angiotensin system

2012 ◽  
Vol 302 (3) ◽  
pp. R313-R320 ◽  
Author(s):  
Curt D. Sigmund
Keyword(s):  
Blood Pressure ◽  
Fluid Intake ◽  
Renin Angiotensin System ◽  
Metabolic Effects ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Intracellular Form ◽  
Efferent Pathways ◽  
The Brain ◽  
Pituitary Adrenal Axis

The purpose of this review is two-fold. First, I will highlight recent advances in our understanding of the mechanisms regulating angiotensin II (ANG II) synthesis in the brain, focusing on evidence that renin is expressed in the brain and is expressed in two forms: a secreted form, which may catalyze extracellular ANG I generation from glial or neuronal angiotensinogen (AGT), and an intracellular form, which may generate intracellular ANG in neurons that may act as a neurotransmitter. Second, I will discuss recent studies that advance the concept that the renin-angiotensin system (RAS) in the brain not only is a potent regulator of blood pressure and fluid intake but may also regulate metabolism. The efferent pathways regulating the blood pressure/dipsogenic effects and the metabolic effects of elevated central RAS activity appear different, with the former being dependent upon the hypothalamic-pituitary-adrenal axis, and the latter being dependent upon an interaction between the brain and the systemic (or adipose) RAS.

scholarly journals EFFECT OF SEQUENTIAL NEPHRON BLOCKING IN COMPARISON WITH THE DOUBLE BLOCKADE OF THE RENIN- ANGIOTENSIN SYSTEM + BISOPROLOL ON CENTRAL SYSTOLIC BLOOD PRESSURE AND ARTERIAL STIFFNESS

2021 ◽  
Vol 39 (Supplement 1) ◽  
pp. e354
Author(s):  
Elizabeth do Espirito Santo Cestari ◽  
Priscilla Galisteu de Mello ◽  
Tatiane de Azevedo Rubio ◽  
Maira Regina de Souza ◽  
Eliangela Gianini Gonzales ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Arterial Stiffness ◽  
Systolic Blood Pressure ◽  
Renin Angiotensin System ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Central Systolic Blood Pressure

scholarly journals Genetic knockdown of brain-derived neurotrophic factor in the nervous system attenuates angiotensin II-induced hypertension in mice

2019 ◽  
Vol 20 (1) ◽  
pp. 147032031983440 ◽  
Author(s):  
Zhongming Zhang ◽  
Yijing Zhang ◽  
Yan Wang ◽  
Shengchen Ding ◽  
Chenhui Wang ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Nervous System ◽  
Angiotensin Ii ◽  
Renin Angiotensin System ◽  
Subfornical Organ ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Peripheral Organs ◽  
Induced Hypertension ◽  
Basal Blood Pressure

Introduction: Brain-derived neurotropic factor (BDNF) is expressed throughout the central nervous system and peripheral organs involved in the regulation of blood pressure, but the systemic effects of BDNF in the control of blood pressure are not well elucidated. Materials and methods: We utilized loxP flanked BDNF male mice to cross with nestin-Cre female mice to generate nerve system BDNF knockdown mice, nestin-BDNF (+/–), or injected Cre adenovirus into the subfornical organ to create subfornical organ BDNF knockdown mice. Histochemistry was used to verify injection location. Radiotelemetry was employed to determine baseline blood pressure and pressor response to angiotensin II (1000 ng/kg/min). Real-time polymerase chain reaction was used to measure the expression of renin–angiotensin system components in the laminal terminalis and peripheral organs. Results: Nestin-BDNF (+/–) mice had lower renin–angiotensin system expression in the laminal terminalis and peripheral organs including the gonadal fat pad, and a lower basal blood pressure. They exhibited an attenuated hypertensive response and a weak or similar modification of renin–angiotensin system component expression to angiotensin II infusion. Subfornical organ BDNF knockdown was sufficient for the attenuation of angiotensin II-induced hypertension. Conclusion: Central BDNF, especially subfornical organ BDNF is involved in the maintenance of basal blood pressure and in augmentation of hypertensive response to angiotensin II through systemic regulation of the expression of renin–angiotensin system molecules.

Role of the Brain Renin-angiotensin System in Blood Pressure Regulation

2007 ◽  
Vol 31 (S1) ◽  
pp. 343-346
Author(s):  
M. V. Varoni ◽  
D. Palomba ◽  
M. P. Demontis ◽  
S. Gianorso ◽  
G. L. Pais ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Renin Angiotensin System ◽  
Blood Pressure Regulation ◽  
Pressure Regulation ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
The Brain

Cardiovascular hypertrophy in diabetic spontaneously hypertensive rats: optimizing blockade of the renin–angiotensin system

2003 ◽  
Vol 104 (4) ◽  
pp. 341-347 ◽  
Author(s):  
Markus LASSILA ◽  
Belinda J. DAVIS ◽  
Terri J. ALLEN ◽  
Louise M. BURRELL ◽  
Mark E. COOPER ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Systolic Blood Pressure ◽  
Calcium Channel ◽  
Spontaneously Hypertensive Rats ◽  
Renin Angiotensin System ◽  
At1 Receptor ◽  
Hypertensive Rats ◽  
Angiotensin System ◽  
Spontaneously Hypertensive ◽  
Renin Angiotensin

The aim of the present study was to compare the antihypertrophic effects of blockade of the renin–angiotensin system (RAS), vasopeptidase inhibition and calcium channel antagonism on cardiac and vascular hypertrophy in diabetic spontaneously hypertensive rats (SHR). SHR with streptozotocin-induced diabetes were treated with one of the following therapies for 32 weeks: the angiotensin-converting enzyme (ACE) inhibitor captopril (100mg/kg); the angiotensin AT1 receptor antagonist valsartan (30mg/kg); a combination of captopril with valsartan; the vasopeptidase inhibitor mixanpril (100mg/kg); or the calcium channel antagonist amlodipine (6mg/kg). Systolic blood pressure and cardiac and mesenteric artery hypertrophy were assessed. Mean systolic blood pressure in diabetic SHR (200±5mmHg) was reduced by captopril (162±5mmHg), valsartan (173±5mmHg), mixanpril (176±2mmHg) and amlodipine (159±4mmHg), and was further reduced by the combination of captopril with valsartan (131±5mmHg). Captopril, valsartan and mixanpril reduced heart and left ventricle weights by approx. 10%. The combination of captopril and valsartan further reduced heart weight (-24%) and left ventricular weight (-29%). Amlodipine did not affect cardiac hypertrophy. Only mixanpril and the combination of captopril and valsartan significantly reduced mesenteric weight. The mesenteric wall/lumen ratio was reduced by all drugs, and to a greater extent by the combination of captopril and valsartan. We conclude that optimizing the blockade of vasoconstrictive pathways such as the RAS, particularly with the combination of ACE inhibition and AT1 receptor antagonism, is associated with antitrophic effects in the context of diabetes and hypertension. In contrast, calcium channel blockade, despite similar effects on blood pressure, confers less antitrophic effects in the diabetic heart and blood vessels.

Abstract 84: Angiotensin II Type 1a Receptor in the Subfornical Organ is Essential for Blood Pressure Regulation and Hydromineral Effects in Mouse Models of Elevated Brain Renin-Angiotensin System Activity.

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Aline Hilzendeger ◽  
Deborah R Davis ◽  
Martin D Cassell ◽  
Allyn L Mark ◽  
Justin L Grobe ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Sodium Intake ◽  
Dna Recombination ◽  
Renin Angiotensin System ◽  
Cre Recombinase ◽  
Subfornical Organ ◽  
Specific Expression ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Conditional Allele

Elevated brain renin-angiotensin system (RAS) activity is necessary to increase blood pressure in many animal models of hypertension. We tested the hypothesis that AT1A receptors (AT1AR) within the subfornical organ (SFO) are required for the phenotypes that result from an increased brain RAS. We examined the effect of SFO-targeted Cre-recombinase mediated ablation of AT1A in mice treated with DOCA-salt (deoxycorticosterone acetate, 50 mg s.c. + ad lib 0.15 M NaCl). Mice homozygous for a conditional allele of the endogenous AT1A gene (AT1ARflox) were administered an adenovirus encoding Cre-recombinase and eGFP (AdCre), or eGFP alone (AdGFP) into the lateral cerebral ventricle, then treated for 3 weeks with DOCA-salt. AdCre reduced DOCA-salt hypertension (AdGFP baseline: 108±3 mmHg; AdGFP pre-DOCA: 104±3; AdGFP post-DOCA: 136±6 vs AdCre baseline: 116±2; Adcre pre-DOCA: 109±3, Adre post-DOCA: 118±5; P≤0.01), polydipsia (AdGFP+DOCA: 20.6±2.1 mL/day; AdCre+DOCA: 11.6±1.1, P<0.05), and sodium intake (AdGFP+DOCA: 2.6±0.3 mEq/day; AdCre+DOCA: 1.8±0.2, P<0.05). AdCre reduced AT1AR mRNA in the SFO (0.4±0.3 fold of AdGFP), without significant effect in the paraventricular or arcuate nuclei, or cortex; this was paralleled by SFO-specific AT1AR genomic DNA recombination. AdCre also caused SFO-specific recombination in ROSA-TdTomato reporter mice. Complementing the DOCA-salt model, we also examined the effect of AT1AR ablation in the SFO of double-transgenic sRA mice. sRA mice exhibit life-long brain-specific angiotensin overproduction via expression of human angiotensinogen via its own promoter and neuron-specific expression of human renin via the synapsin promoter. In sRA mice bred onto the AT1A conditional genetic background, AdCre significantly attenuated the polydipsia (AdGFP: -0.2±2; AdCre: -9.7±2.6 mL/day) and sodium intake (AdGFP: +0.2±0.7; AdCre: -1.3±0.4 mEq/day). Blood pressure measures are in progress. Together, these data highlight the involvement of SFO AT1A receptors in blood pressure in DOCA-salt model and additionally in hydromineral balance in two different models of increased brain RAS activity.

scholarly journals Losartan prevents the elevation of blood pressure in adipose-PRR deficient female mice while elevated circulating sPRR activates the renin-angiotensin system

2019 ◽  
Vol 316 (3) ◽  
pp. H506-H515 ◽  
Author(s):  
Eva Gatineau ◽  
Dianne M. Cohn ◽  
Marko Poglitsch ◽  
Analia S. Loria ◽  
Ming Gong ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Systolic Blood Pressure ◽  
Renin Angiotensin System ◽  
Soluble Form ◽  
Ang Ii ◽  
High Fat ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Female Mice ◽  
Prorenin Receptor

Deletion of the prorenin receptor (PRR) in adipose tissue elevates systolic blood pressure (SBP) and the circulating soluble form of PRR (sPRR) in male mice fed a high-fat (HF) diet. However, sex differences in the contribution of adipose-PRR and sPRR to the regulation of the renin-angiotensin system (RAS) in key organs for blood pressure control are undefined. Therefore, we assessed blood pressure and the systemic and intrarenal RAS status in adipose-PRR knockout (KO) female mice. Blockade of RAS with losartan blunted SBP elevation in HF diet-fed adipose-PRR KO mice. ANG II levels were significantly increased in the renal cortex of HF diet-fed adipose-PRR KO female mice, but not systemically. HF diet-fed adipose-PRR KO mice exhibited higher vasopressin levels, water retention, and lower urine output than wild-type (WT) mice. The results also showed that deletion of adipose-PRR increased circulating sPRR and total hepatic sPRR contents, suggesting the liver as a major source of elevated plasma sPRR in adipose-PRR KO mice. To mimic the elevation of circulating sPRR and define the direct contribution of systemic sPRR to the regulation of the RAS and vasopressin, C57BL/6 female mice fed a standard diet were infused with recombinant sPRR. sPRR infusion increased plasma renin levels, renal and hepatic angiotensinogen expression, and vasopressin. Together, these results demonstrate that the deletion of adipose-PRR induced an elevation of SBP likely mediated by an intrarenal ANG II-dependent mechanism and that sPRR participates in RAS regulation and body fluid homeostasis via its capacity to activate the RAS and increase vasopressin levels. NEW & NOTEWORTHY The elevation of systolic blood pressure appears to be primarily mediated by cortical ANG II in high-fat diet-fed adipose-prorenin receptor knockout female mice. In addition, our data support a role for soluble prorenin receptor in renin-angiotensin system activation and vasopressin regulation.

Role of the Brain Iso-Renin-Angiotensin System in Experimental Hypertension in Rats

1981 ◽  
Vol 61 (2) ◽  
pp. 175-180 ◽  
Author(s):  
Hiromichi Suzuki ◽  
Kazuoki Kondo ◽  
Michiko Handa ◽  
Takao Saruta
Keyword(s):  
Blood Pressure ◽  
Plasma Renin Activity ◽  
Renin Angiotensin System ◽  
Plasma Renin ◽  
Renin Activity ◽  
Cerebral Ventricles ◽  
Hypertensive Rats ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
The Brain

1. To examine the possible participation of the brain iso-renin-angiotensin system in the control of blood pressure, as well as in the regulation of plasma renin activity, saralasin and captopril were injected into the cerebral ventricles of three types of experimental hypertensive rats with different plasma renin profiles. 2. Injection of saralasin and captopril into the cerebral ventricles resulted in a significant decrease in blood pressure of two-kidney, one-clip Goldblatt hypertensive rats (11 ± 2 and 9 ± 3 mmHg respectively) and that of spontaneously hypertensive rats (13 ± 2 and 12 ± 2 mmHg respectively), but in deoxycorticosterone (DOC)-salt hypertensive rats injection of these two agents showed a significant increase in blood pressure (13 ± 2 and 12 ± 3 mmHg respectively). 3. The plasma renin activity was markedly decreased after injection of saralasin and captopril into the cerebral ventricles of two-kidney, one-clip Goldblatt hypertensive rats. Conversely, in DOC-salt hypertensive rats, the plasma renin activity was markedly increased after injection of these two agents. In spontaneously hypertensive rats these agents caused no significant change in plasma renin activity. 4. These findings suggest that the brain iso-renin-angiotensin system participates in the central regulation of blood pressure and may be responsible for modulation of the peripheral renin-angiotensin system.

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