scholarly journals Brain renin-angiotensin system blockade by systemically active aminopeptidase A inhibitors: A potential treatment of salt-dependent hypertension

2004 ◽  
Vol 101 (20) ◽  
pp. 7775-7780 ◽  
Author(s):  
M.-C. Fournie-Zaluski ◽  
C. Fassot ◽  
B. Valentin ◽  
D. Djordjijevic ◽  
A. Reaux-Le Goazigo ◽  
...  
Keyword(s):  
Renin Angiotensin System ◽  
Potential Treatment ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Aminopeptidase A

A new strategy for treating hypertension by blocking the activity of the brain renin–angiotensin system with aminopeptidase A inhibitors

2014 ◽  
Vol 127 (3) ◽  
pp. 135-148 ◽  
Author(s):  
Ji Gao ◽  
Yannick Marc ◽  
Xavier Iturrioz ◽  
Vincent Leroux ◽  
Fabrice Balavoine ◽  
...  
Keyword(s):  
Antihypertensive Agents ◽  
Renin Angiotensin System ◽  
Site Directed Mutagenesis ◽  
Hypertensive Rats ◽  
Vasopressin Release ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Obesity And Diabetes ◽  
Aminopeptidase A ◽  
The Brain

Hypertension affects one-third of the adult population and is a growing problem due to the increasing incidence of obesity and diabetes. Brain RAS (renin–angiotensin system) hyperactivity has been implicated in the development and maintenance of hypertension in several types of experimental and genetic hypertension animal models. We have identified in the brain RAS that APA (aminopeptidase A) and APN (aminopeptidase N), two membrane-bound zinc metalloproteases, are involved in the metabolism of AngII (angiotensin II) and AngIII (angiotensin III) respectively. The present review summarizes the main findings suggesting that AngIII plays a predominant role in the brain RAS in the control of BP (blood pressure). We first explored the organization of the APA active site by site-directed mutagenesis and molecular modelling. The development and the use in vivo of specific and selective APA and APN inhibitors EC33 and PC18 respectively, has allowed the demonstration that brain AngIII generated by APA is one of the main effector peptides of the brain RAS, exerting a tonic stimulatory control over BP in conscious hypertensive rats. This identified brain APA as a potential therapeutic target for the treatment of hypertension, which has led to the development of potent orally active APA inhibitors, such as RB150. RB150 administered orally in hypertensive DOCA (deoxycorticosteroneacetate)-salt rats or SHRs (spontaneously hypertensive rats) crosses the intestinal, hepatic and blood–brain barriers, enters the brain, generates two active molecules of EC33 which inhibit brain APA activity, block the formation of brain AngIII and normalize BP for several hours. The decrease in BP involves two different mechanisms: a decrease in vasopressin release into the bloodstream, which in turn increases diuresis resulting in a blood volume reduction that participates in the decrease in BP and/or a decrease in sympathetic tone, decreasing vascular resistance. RB150 constitutes the prototype of a new class of centrally acting antihypertensive agents and is currently being evaluated in a Phase Ib clinical trial.

The Renin Angiotensin System as a potential treatment target for Traumatic Brain Injury

2022 ◽  
Author(s):  
Daniel Hendrik Baron ◽  
Olivia A Skrobot ◽  
Jennifer C Palmer ◽  
Kanchan Sharma ◽  
Patrick Kehoe
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Renin Angiotensin System ◽  
Potential Treatment ◽  
Treatment Target ◽  
Angiotensin System ◽  
Renin Angiotensin

scholarly journals Potential Roles of the Renin-Angiotensin System in the Pathogenesis and Treatment of COVID-19

2020 ◽  
Vol 2020 ◽  
pp. 1-7
Author(s):  
Ling Lu ◽  
Xiaomei Liu ◽  
Rong Jin ◽  
Renzheng Guan ◽  
Rongjun Lin ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Treatment Options ◽  
Renin Angiotensin System ◽  
Symptomatic Treatment ◽  
Potential Treatment ◽  
Converting Enzyme ◽  
Angiotensin System ◽  
Angiotensin Converting Enzyme 2 ◽  
Renin Angiotensin ◽  
Major Treatment

The spread of pathogenic severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) poses a global health emergency. Based on the symptomatic treatment and supporting therapy, prevention of complications is the major treatment option. Therefore, it is necessary to illustrate the potential mechanisms for the pathogenesis of COVID-19. Angiotensin-converting enzyme 2 (ACE2), the major receptor of SARS-CoV-2, is one of the major members of the renin-angiotensin system (RAS). In this review, we aimed to summarize the crucial roles of ACE2 in the pathogenesis of COVID-19, followed by illustrating potential treatment options relating to ACE2 and the RAS.

P4473Brain renin-angiotensin system blockade with firibastat, an orally active, central acting aminopeptidase A inhibitor prodrug prevents cardiac dysfunction after myocardial infarction in mice

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
S Boitard-Joanne ◽  
Y Marc ◽  
M Keck ◽  
N Mougenot ◽  
O Agbulut ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Dysfunction ◽  
Enzyme Inhibitor ◽  
Diastolic Pressure ◽  
Renin Angiotensin System ◽  
Left Ventricular ◽  
Mrna Levels ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Aminopeptidase A

Abstract Introduction Brain renin-angiotensin system (RAS) hyperactivity has been implicated in sympathetic hyperactivity and progressive left ventricular (LV) dysfunction after myocardial infarction (MI). Brain angiotensin III, generated by aminopeptidase A (APA), is one of the main effector peptides of the brain RAS in the control of cardiac function. Purpose We hypothesized that orally administered firibastat (previously named RB150), an orally central acting APA inhibitor prodrug, would attenuate heart failure (HF) development after MI in mice, by blocking brain RAS hyperactivity. Methods Two days after MI induced by the left anterior descending artery ligation, adult male CD1 mice were randomized to three groups, for four to eight weeks of oral treatment with vehicle (MI+vehicle), firibastat (150 mg/kg; MI+firibastat) or the angiotensin I converting enzyme inhibitor enalapril (1 mg/kg; MI+enalapril) as a positive control. Results From one to four weeks post-MI, brain APA hyperactivity occurred, contributing to brain RAS hyperactivity. Firibastat treatment during four weeks after MI normalized brain APA hyperactivity, with a return to the control values measured in the sham group. Four and six weeks after MI, MI+firibastat mice had a significant lower LV end-diastolic pressure, LV end-systolic diameter and volume, and a higher LV ejection fraction than MI+vehicle mice. Moreover, the mRNA levels of biomarkers of HF (Myh7, Bnp and Anf) were significantly lower following firibastat treatment. For a similar infarct size, the peri-infarct area of MI+firibastat mice displayed lower levels of mRNA for markers of fibrosis such Ctgf and collagen types I and III than MI+vehicle mice. Conclusions Chronic oral firibastat administration after MI in mice normalizes brain APA hyperactivity, thereby normalizing brain RAS hyperactivity, whilst preventing cardiac dysfunction and attenuating cardiac hypertrophy and fibrosis. Acknowledgement/Funding INSERM, College de France, ANR LabCom, and Quantum Genomics

Characterization of renin-angiotensin system enzyme activities in cultured mouse podocytes

2007 ◽  
Vol 293 (1) ◽  
pp. F398-F407 ◽  
Author(s):  
Juan Carlos Q. Velez ◽  
Alison M. Bland ◽  
John M. Arthur ◽  
John R. Raymond ◽  
Michael G. Janech
Keyword(s):  
Mesangial Cells ◽  
Renin Angiotensin System ◽  
Ang Ii ◽  
Glomerular Injury ◽  
Renin Substrate ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Neprilysin Inhibitor ◽  
Aminopeptidase A ◽  
Aminopeptidase A Inhibitor

Intraglomerular ANG II has been linked to glomerular injury. However, little is known about the contribution of podocytes (POD) to intraglomerular ANG II homeostasis. The aim of the present study was to examine the processing of angiotensin substrates by cultured POD. Our approach was to use matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry for peptide determination from conditioned cell media and customized AQUA peptides for quantification. Immortalized mouse POD were incubated with 1-2 μM ANG I, ANG II, or the renin substrate ANG-(1-14) for different time intervals and coincubated in parallel with various inhibitors. Human mesangial cells (MES) were used as controls. POD incubated with 1 μM ANG I primarily formed ANG-(1-9) and ANG-(1-7). In contrast, MES incubated with ANG I primarily generated ANG II. In POD, ANG-(1-7) was the predominant product, and its formation was inhibited by a neprilysin inhibitor. Modest angiotensin-converting enzyme (ACE) activity was also detected in POD, although only after cells were incubated with 2 μM ANG I. In addition, we observed that POD degraded ANG II into ANG III and ANG-(1-7). An aminopeptidase A inhibitor inhibited ANG III formation, and an ACE2 inhibitor led to ANG II accumulation. Furthermore, we found that POD converted ANG-(1-14) to ANG I and ANG-(1-7). This conversion was inhibited by a renin inhibitor. These findings demonstrate that POD express a functional intrinsic renin-angiotensin system characterized by neprilysin, aminopeptidase A, ACE2, and renin activities, which predominantly lead to ANG-(1-7) and ANG-(1-9) formation, as well as ANG II degradation. These findings may reflect a specific role of POD in maintenance of intraglomerular renin-angiotensin system balance.

Fifty years of research on the brain renin–angiotensin system: what have we learned?

2021 ◽  
Vol 135 (14) ◽  
pp. 1727-1731
Author(s):  
Edwyn O. Cruz-López ◽  
Estrellita Uijl ◽  
A.H. Jan Danser
Keyword(s):  
Brain Tissue ◽  
Nervous Activity ◽  
Renin Angiotensin System ◽  
Sympathetic Nervous Activity ◽  
Ang Ii ◽  
Angiotensin System ◽  
Future Studies ◽  
Renin Angiotensin ◽  
Aminopeptidase A ◽  
The Brain

Abstract Although the existence of a brain renin–angiotensin system (RAS) had been proposed five decades ago, we still struggle to understand how it functions. The main reason for this is the virtual lack of renin at brain tissue sites. Moreover, although renin’s substrate, angiotensinogen, appears to be synthesized locally in the brain, brain angiotensin (Ang) II disappeared after selective silencing of hepatic angiotensinogen. This implies that brain Ang generation depends on hepatic angiotensinogen after all. Rodrigues et al. (Clin Sci (Lond) (2021) 135:1353–1367) generated a transgenic mouse model overexpressing full-length rat angiotensinogen in astrocytes, and observed massively elevated brain Ang II levels, increased sympathetic nervous activity and vasopressin, and up-regulated erythropoiesis. Yet, blood pressure and kidney function remained unaltered, and surprisingly no other Ang metabolites occurred in the brain. Circulating renin was suppressed. This commentary critically discusses these findings, concluding that apparently in the brain, overexpressed angiotensinogen can be cleaved by an unidentified non-renin enzyme, yielding Ang II directly, which then binds to Ang receptors, allowing no metabolism by angiotensinases like ACE2 and aminopeptidase A. Future studies should now unravel the identity of this non-renin enzyme, and determine whether it also contributes to Ang II generation at brain tissue sites in wildtype animals. Such studies should also re-evaluate the concept that Ang-(1-7) and Ang III, generated by ACE2 and aminopeptidase A, respectively, have important functions in the brain.

scholarly journals Mouse glomerular epithelial cells in culture with features of podocytes in vivo express aminopeptidase A and angiotensinogen but not other components of the renin-angiotensin system.

1997 ◽  
Vol 8 (5) ◽  
pp. 706-719
Author(s):  
S Mentzel ◽  
J P Van Son ◽  
A S De Jong ◽  
H B Dijkman ◽  
R A Koene ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Monoclonal Antibodies ◽  
Angiotensin Ii ◽  
Epithelial Cells ◽  
Mrna Expression ◽  
Renin Angiotensin System ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Aminopeptidase A

The binding of antibodies to podocytic antigens such as the Heymann antigen or aminopeptidase A may lead to the induction of a membranous glomerulonephritis in several species. To study the possible future interactions of antibodies with antigens on these podocytes, epithelial cells from isolated mouse glomeruli were cultured. By indirect immunofluorescence, the cells were positive for cytokeratin, vimentin, desmin, and the ZO-1 protein, a component of the tight junction complex. When rat monoclonal antibodies were used, the cells were also positive for the hydrolases aminopeptidase A and dipeptidyl peptidase IV, and they stained with ASD-33, a monoclonal antibody that recognized an epitope only present on the cell membranes of mouse podocytes. They were negative for the von Willebrand factor and did not stain with a monoclonal antibody (ASD-13) that binds to endothelial cells of glomeruli and peritubular capillaries. By electron microscopy, the cells showed tight junctions but lacked Weibel Palade bodies (endothelium), desmosomes, and cilia (parietal epithelium). The mRNA expression of several components of the renin-angiotensin system was also examined, and some factors indirectly coupled to the renin-angiotensin system component angiotensin II in this podocytic culture by RT-PCR analysis. mRNA Expression for the angiotensin II degrading hydrolase aminopeptidase A and angiotensinogen was found, but this was not found for any other component of this system, such as renin, angiotensin-converting enzyme, or the angiotensin II receptors AT1a, AT1b, and AT2. Low mRNA expression for dipeptidyl peptidase IV was observed. In addition, expression of the growth factors transforming growth factor-beta and interleukin-7, and the extracellular matrix components fibronectin, laminin B2, perlecan, and collagen IV alpha 1, was observed. Given these characteristics, a glomerular epithelial cell culture with features of podocytes in vivo that will allow future studies on the interaction of anti-aminopeptidase A monoclonal antibodies and angiotensin II with aminopeptidase A was established. This is of interest in light of the observation that injection of mice with anti-aminopeptidase A antibodies causes an acute albuminuria.

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