Angiotensin generation in the brain: a re-evaluation

2018 ◽  
Vol 132 (8) ◽  
pp. 839-850 ◽  
Author(s):  
Estrellita Uijl ◽  
Liwei Ren ◽  
A.H. Jan Danser
Keyword(s):  
Blood Brain Barrier ◽  
Renin Angiotensin System ◽  
Brain Barrier ◽  
Ang Ii ◽  
Independent Manner ◽  
Neurogenic Hypertension ◽  
Local Synthesis ◽  
Blood Brain Barrier Disruption ◽  
Blood Brain ◽  
The Brain

The existence of a so-called brain renin-angiotensin system (RAS) is controversial. Given the presence of the blood–brain barrier, angiotensin generation in the brain, if occurring, should depend on local synthesis of renin and angiotensinogen. Yet, although initially brain-selective expression of intracellular renin was reported, data in intracellular renin knockout animals argue against a role for this renin in angiotensin generation. Moreover, renin levels in brain tissue at most represented renin in trapped blood. Additionally, in neurogenic hypertension brain prorenin up-regulation has been claimed, which would generate angiotensin following its binding to the (pro)renin receptor. However, recent studies reported no evidence for prorenin expression in the brain, nor for its selective up-regulation in neurogenic hypertension, and the (pro)renin receptor rather displays RAS-unrelated functions. Finally, although angiotensinogen mRNA is detectable in the brain, brain angiotensinogen protein levels are low, and even these low levels might be an overestimation due to assay artefacts. Taken together, independent angiotensin generation in the brain is unlikely. Indeed, brain angiotensin levels are extremely low, with angiotensin (Ang) I levels corresponding to the small amounts of Ang I in trapped blood plasma, and Ang II levels at most representing Ang II bound to (vascular) brain Ang II type 1 receptors. This review concludes with a unifying concept proposing the blood origin of angiotensin in the brain, possibly resulting in increased levels following blood–brain barrier disruption (e.g. due to hypertension), and suggesting that interfering with either intracellular renin or the (pro)renin receptor has consequences in an RAS-independent manner.

scholarly journals Impact of the Renin–Angiotensin System on the Endothelium in Vascular Dementia: Unresolved Issues and Future Perspectives

2020 ◽  
Vol 21 (12) ◽  
pp. 4268 ◽  
Author(s):  
Fatima Y. Noureddine ◽  
Raffaele Altara ◽  
Fan Fan ◽  
Andriy Yabluchanskiy ◽  
George W. Booz ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Vascular Dementia ◽  
Blood Brain Barrier ◽  
Renin Angiotensin System ◽  
Brain Barrier ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Blood Brain ◽  
Body Tissues ◽  
The Brain

The effects of the renin–angiotensin system (RAS) surpass the renal and cardiovascular systems to encompass other body tissues and organs, including the brain. Angiotensin II (Ang II), the most potent mediator of RAS in the brain, contributes to vascular dementia via different mechanisms, including neuronal homeostasis disruption, vascular remodeling, and endothelial dysfunction caused by increased inflammation and oxidative stress. Other RAS components of emerging significance at the level of the blood–brain barrier include angiotensin-converting enzyme 2 (ACE2), Ang(1–7), and the AT2, Mas, and AT4 receptors. The various angiotensin hormones perform complex actions on brain endothelial cells and pericytes through specific receptors that have either detrimental or beneficial actions. Increasing evidence indicates that the ACE2/Ang(1–7)/Mas axis constitutes a protective arm of RAS on the blood–brain barrier. This review provides an update of studies assessing the different effects of angiotensins on cerebral endothelial cells. The involved signaling pathways are presented and help highlight the potential pharmacological targets for the management of cognitive and behavioral dysfunctions associated with vascular dementia.

scholarly journals Neuroinflammation in Response to Intracerebral Injections of Different HMGB1 Redox Isoforms

2018 ◽  
Vol 10 (3) ◽  
pp. 215-227 ◽  
Author(s):  
Hannah Aucott ◽  
Johan Lundberg ◽  
Henna Salo ◽  
Lena Klevenvall ◽  
Peter Damberg ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Inflammatory Responses ◽  
Brain Barrier ◽  
Dark Agouti ◽  
Independent Manner ◽  
Barrier Disruption ◽  
Blood Brain Barrier Disruption ◽  
Central Nervous System Dysfunction ◽  
Blood Brain ◽  
Brain Barrier Disruption

Background: Neuroinflammation triggered by infection or trauma is the cause of central nervous system dysfunction. High-mobility group box 1 protein (HMGB1), released from stressed and dying brain cells, is a potent neuroinflammatory mediator. The proinflammatory functions of HMGB1 are tightly regulated by post-translational redox modifications, and we here investigated detailed neuroinflammatory responses induced by the individual redox isoforms. Methods: Male Dark Agouti rats received a stereotactic injection of saline, lipopolysaccharide, disulfide HMGB1, or fully reduced HMGB1, and were accessed for blood-brain barrier modifications using magnetic resonance imaging (MRI) and inflammatory responses by immunohistochemistry. Results and Conclusions: Significant blood-brain barrier disruption appeared 24 h after injection of lipopolysaccharide, disulfide HMGB1, or fully reduced HMGB1 compared to controls, as assessed in post-gadolinium T1-weighted MRI images and confirmed by increased uptake of FITC-conjugated dextran. Immunohistochemistry revealed that both HMGB1 isoforms also induced a local production of IL-1β. Additionally, disulfide HMGB1 increased major histocompatibility complex class II expression and apoptosis. Together, the results demonstrate that extracellular, cerebral HMGB1 causes significant blood-brain barrier disruption in a redox-independent manner and activates several components of neuroinflammation. Blocking HMGB1 might potentially improve clinical outcome in conditions such as stroke and traumatic brain injury.

scholarly journals The Non-peptide Angiotensin-(1–7) Mimic AVE 0991 Attenuates Delayed Neurocognitive Recovery After Laparotomy by Reducing Neuroinflammation and Restoring Blood-Brain Barrier Integrity in Aged Rats

2021 ◽  
Vol 13 ◽  
Author(s):  
Xinning Mi ◽  
Yiyun Cao ◽  
Yue Li ◽  
Yitong Li ◽  
Jingshu Hong ◽  
...  
Keyword(s):  
Matrix Metalloproteinase ◽  
Blood Brain Barrier ◽  
Older Adult ◽  
Renin Angiotensin System ◽  
Receptor Expression ◽  
Adult Patients ◽  
Brain Barrier ◽  
Ang Ii ◽  
Matrix Metalloproteinase 3 ◽  
Blood Brain

Delayed neurocognitive recovery (dNCR) after surgery is a common postoperative complication in older adult patients. Our previous studies have demonstrated that cognitive impairment after surgery involves an increase in the brain renin-angiotensin system (RAS) activity, including overactivation of the angiotensin 2/angiotensin receptor-1 (Ang II/AT1) axis, which provokes the disruption of the hippocampal blood-brain barrier (BBB). Nevertheless, the potential role of the counter-regulatory RAS axis, the Ang-(1–7)/Mas pathway, in dNCR remains unknown. Using an aged rat model of dNCR, we dynamically investigated the activity of both axes of the RAS following laparotomy. AVE 0991, a nonpeptide analog of Ang-(1–7), was administered intranasally immediately after laparotomy. We found that the elevation of Ang II, induced by surgery was accompanied by a decrease of Ang-(1–7) in the hippocampus, but not in the circulation. Surgery also significantly downregulated hippocampal Mas receptor expression at 24 h postsurgery. Mas activation with intranasal AVE 0991 treatment significantly improved hippocampus-dependent learning and memory deficits induced by surgery. Furthermore, it attenuated hippocampal neuroinflammation, as shown by the decreased level of the microglial activation marker cluster of differentiation 11b (CD11b) and the decreased production of several inflammatory molecules. Along with these beneficial effects, the AVE 0991 treatment also alleviated the imbalance between matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteinase-3 (TIMP-3), modulated the expression of occludin, and alleviated the IgG extravasation, thereby restoring the integrity of the BBB. In conclusion, these data indicate that activation of Mas by AVE 0991 attenuates dNCR after surgery by reducing neuroinflammation and restoring BBB integrity. Our findings suggest that the Ang-(1–7)/Mas pathway may be a novel therapeutic target for treating dNCR after surgery in older adult patients.

scholarly journals Increased nanoparticle-loaded exogenous macrophage migration into the brain following PDT-induced blood-brain barrier disruption

2013 ◽  
Vol 45 (8) ◽  
pp. 524-532 ◽  
Author(s):  
Steen J. Madsen ◽  
H. Michael Gach ◽  
Seok Jin Hong ◽  
Francisco A. Uzal ◽  
Qian Peng ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Macrophage Migration ◽  
Barrier Disruption ◽  
Blood Brain Barrier Disruption ◽  
Blood Brain ◽  
Brain Barrier Disruption ◽  
The Brain

Blood-brain barrier disruption in humans using an implantable ultrasound device: quantification with MR images and correlation with local acoustic pressure

2020 ◽  
Vol 132 (3) ◽  
pp. 875-883 ◽  
Author(s):  
Nicolas Asquier ◽  
Guillaume Bouchoux ◽  
Michael Canney ◽  
Cyril Martin ◽  
Bruno Law-Ye ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Acoustic Pressure ◽  
Brain Barrier ◽  
Mr Images ◽  
Barrier Disruption ◽  
Ultrasound Device ◽  
Blood Brain Barrier Disruption ◽  
Blood Brain ◽  
Brain Barrier Disruption ◽  
The Brain

OBJECTIVEOne of the goals in this study was to set up a semiautomatic method to estimate blood-brain barrier disruption obtained in patients with glioblastoma by using an implantable, unfocused, ultrasound device. Another goal was to correlate the probability of significant ultrasound-induced signal enhancement (SUISE) with local acoustic pressure in the brain.METHODSGd-enhanced MR images acquired before and after ultrasound treatments were analyzed prospectively. The image sets were segmented, normalized, and coregistered to evaluate contrast enhancement. The volume of SUISE was calculated with voxels labeled as gray or white matter, in a cylindrical region of interest, and with enhancement above a given threshold. To validate the method, the resulting volumes of SUISE were compared to qualitative grades previously assigned by 3 clinicians for 40 ultrasound treatments in 15 patients. A parametric study was performed to optimize the algorithm prediction of the qualitative grades. The 3D acoustic field in the brain was estimated from measurements in water combined with simulations accounting for ultrasound attenuation in brain and overlaid on each MR image to correlate local acoustic pressure with the probability of SUISE (defined as enhancement > 10%).RESULTSThe algorithm predicted grade 2 or 3 and grade 3 openings with areas under the receiver operating characteristic curve of 0.831 and 0.995, respectively. The probability of SUISE was correlated with local acoustic pressure (R2 = 0.98) and was 3.33 times higher for gray matter than for white matter.CONCLUSIONSAn algorithm for evaluating blood-brain barrier disruption was validated and can be used for future clinical trials to further understand and quantify this technique in humans.Clinical trial registration no.: NCT02253212 (clinicaltrials.gov)

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