scholarly journals The intrarenal renin-angiotensin system in hypertension: Insights from mathematical modelling

2021 ◽  
Author(s):  
Delaney Smith ◽  
Anita Layton
Keyword(s):  
Computational Modelling ◽  
Renin Angiotensin System ◽  
Ang Ii ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Clinical Hypertension ◽  
Induced Hypertension ◽  
Intrarenal Ras

The renin-angiotensin system (RAS) plays a pivotal role in the maintenance of volume homeostasis and blood pressure. In addition to the well-studied systemic RAS, local RAS have been documented in various tissues, including the kidney. Given the role of the intrarenal RAS in the pathogenesis of hypertension, a role established via various pharmacologic and genetic studies, substantial efforts have been made to unravel the processes that govern intrarenal RAS activity. In particular, several mechanisms have been proposed to explain the rise in intrarenal angiotensin II (Ang II) that accompanies Ang II infusion, including increased angiotensin type 1 receptor (AT1R)-mediated uptake of Ang II and enhanced intrarenal Ang II production. However, experimentally isolating their contribution to the intrarenal accumulation of Ang II in Ang II--induced hypertension is challenging, given that they are fundamentally connected. Computational modelling is advantageous because the feedback underlying each mechanism can removed and the effect on intrarenal Ang II can be studied. In this work, the mechanisms governing the intrarenal accumulation of Ang II during Ang II infusion experiments are delineated and the role of the intrarenal RAS in Ang II-induced hypertension is studied. To accomplish this, a compartmental ODE model of the systemic and intrarenal RAS is developed and Ang II infusion experiments are simulated. Simulations indicate that AT1R-mediated uptake of Ang II is the primary mechanism by which Ang II accumulates in the kidney during Ang II infusion. Enhanced local Ang II production is unnecessary. The results demonstrate the role of the intrarenal RAS in the pathogenesis of Ang II-induced hypertension and consequently, clinical hypertension associated with an overactive RAS.

Abstract 227: The Protective Effect of Kidney-Specific ACE Inhibition Against Chronic Angiotensin II Infusions is Associated with Blunted Intrarenal Renin-Angiotensin System Activation

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Jorge F Giani ◽  
Tea Djandjoulia ◽  
Nicholas Fetcher ◽  
Sebastien Fuchs ◽  
Dale M Seth ◽  
...  
Keyword(s):  
Renin Angiotensin System ◽  
Fold Increase ◽  
Ace Inhibition ◽  
Sham Operation ◽  
Ang Ii ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Intrarenal Ras ◽  
Failed Induction

Introduction: The responses to chronic angiotensin (Ang) II infusions of gene-targeted mice lacking kidney angiotensin-converting enzyme (ACE), in terms of intrarenal Ang II accumulation, hypertension, sodium and water retention are all blunted or absent. The objective of this study was to determine if these reduced responses were associated with changes in the intrarenal renin-angiotensin system (RAS). METHODS: Mice lacking intrarenal ACE (ACE10/10) were generated by targeted homologous recombination placing the expression of ACE only in macrophages. As a result, these mice have normal circulating ACE levels, but no kidney ACE. Wild-type (WT) mice of the same background (C57Bl/J) served as controls. Mice were subjected to sham-operation or subcutaneous infusion of Ang II for two weeks (n=6-10, 400 ng/kg/min via osmotic minipump). Mean arterial pressure (MAP) was followed by telemetry. At the end of the experiment, the kidneys were collected for analysis. Ang II content was measured by RIA. Renal abundance of ACE, angiotensinogen (AGT) and Ang II receptor type 1 (AT1R) were determined by Western Blot in total kidney homogenates. Results: At baseline, the MAP of WT and ACE 10/10 mice was similar 110 ± 4 mmHg vs. 109 ± 3 mmHg respectively (p>0.05). However, when subjected to chronic Ang II infusions, the hypertensive response was blunted in ACE 10/10 mice (129 ± 6 mmHg) vs. WT (146 ± 5 mmHg; P<0.05). Also, intrarenal Ang II accumulation was lower in ACE10/10 mice (724 ± 81 fmol/g) vs. WT (1130 ± 105 fmol/g, p<0.05). In non-treated mice, intrarenal RAS components analysis revealed that the absence of ACE in ACE10/10 mice was accompanied by a significant reduction in AGT (0.41 ± 0.06) and increased AT1R expression (1.32 ± 0.05) when compared to WT (normalized to 1.00, p<0.05 in both instances). Importantly, after chronic Ang II infusions, AGT, ACE and AT1R expression increased in WT (1.36, 1.26 and 1.17 fold increase respectively compared to non-treated WT, p<0.05) but not in the ACE10/10 mice (1.19, 1.06, 0.89 fold increase respectively compared to non-treated ACE10/10, p>0.05). Conclusion: The blunted hypertension and Ang II accumulation of mice devoid of kidney ACE in response to Ang II infusions is associated with a failed induction of renal AGT and the AT1R.

scholarly journals Intrarenal mouse renin-angiotensin system during ANG II-induced hypertension and ACE inhibition

2010 ◽  
Vol 298 (1) ◽  
pp. F150-F157 ◽  
Author(s):  
Romer A. Gonzalez-Villalobos ◽  
Ryousuke Satou ◽  
Naro Ohashi ◽  
Laura C. Semprun-Prieto ◽  
Akemi Katsurada ◽  
...  
Keyword(s):  
Renin Angiotensin System ◽  
Ace Inhibition ◽  
Ang Ii ◽  
Male Mice ◽  
Rt Pcr ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Induced Hypertension ◽  
Angiotensin Type

Angiotensin-converting enzyme (ACE) inhibition (ACEi) ameliorates the development of hypertension and the intrarenal ANG II augmentation in ANG II-infused mice. To determine if these effects are associated with changes in the mouse intrarenal renin-angiotensin system, the expression of angiotensinogen (AGT), renin, ACE, angiotensin type 1 receptor (AT1R) mRNA (by quanitative RT-PCR) and protein [by Western blot (WB) and/or immunohistochemistry (IHC)] were analyzed. C57BL/6J male mice (9–12 wk old) were distributed as controls ( n = 10), ANG II infused (ANG II = 8, 400 ng·kg−1·min−1 for 12 days), ACEi only (ACEi = 10, lisinopril, 100 mg/l), and ANG II infused + ACEi (ANG II + ACEi = 11). When compared with controls (1.00), AGT protein (by WB) was increased by ANG II (1.29 ± 0.13, P < 0.05), and this was not prevented by ACEi (ACEi + ANG II, 1.31 ± 0.14, P < 0.05). ACE protein (by WB) was increased by ANG II (1.21 ± 0.08, P < 0.05), and it was reduced by ACEi alone (0.88 ± 0.07, P < 0.05) or in combination with ANG II (0.80 ± 0.07, P < 0.05). AT1R protein (by WB) was increased by ANG II (1.27 ± 0.06, P < 0.05) and ACEi (1.17 ± 0.06, P < 0.05) but not ANG II + ACEi [1.15 ± 0.06, not significant (NS)]. Tubular renin protein (semiquantified by IHC) was increased by ANG II (1.49 ± 0.23, P < 0.05) and ACEi (1.57 ± 0.15, P < 0.05), but not ANG II + ACEi (1.10 ± 0.15, NS). No significant changes were observed in AGT, ACE, or AT1R mRNA. In summary, reduced responses of intrarenal tubular renin, ACE, and the AT1R protein to the stimulatory effects of chronic ANG II infusions, in the presence of ACEi, are associated with the effects of this treatment to ameliorate augmentations in blood pressure and intrarenal ANG II content during ANG II-induced hypertension.

scholarly journals Angiotensin II Receptor Type 1-Mediated Vascular Oxidative Stress and Proinflammatory Gene Expression in Aldosterone-Induced Hypertension: The Possible Role of Local Renin-Angiotensin System

Endocrinology ◽  
2007 ◽  
Vol 148 (4) ◽  
pp. 1688-1696 ◽  
Author(s):  
Yuki Hirono ◽  
Takanobu Yoshimoto ◽  
Noriko Suzuki ◽  
Toru Sugiyama ◽  
Maya Sakurada ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Renin Angiotensin System ◽  
Aortic Tissue ◽  
Ang Ii ◽  
Converting Enzyme ◽  
Angiotensin System ◽  
Renin Angiotensin

Recently, aldosterone has been shown to activate local renin-angiotensin system in vitro. To elucidate the potential role of local renin-angiotensin system in aldosterone-induced cardiovascular injury, we investigated the effects of selective mineralocorticoid receptor (MR) antagonist eplerenone (EPL), angiotensin (Ang) II type 1 receptor antagonist candesartan (ARB), and superoxide dismutase mimetic tempol (TEM) on the development of hypertension, vascular injury, oxidative stress, and inflammatory-related gene expression in aldosterone-treated hypertensive rats. The increased systolic blood pressure and vascular inflammatory changes were attenuated by cotreatment either with EPL, ARB, or TEM. Aldosterone increased angiotensin-converting enzyme expression in the aortic tissue; its effects were blocked by EPL but not by ARB or TEM. Aldosterone also increased Ang II contents in the aortic tissue in the presence of low circulating Ang II concentrations. Aldosterone induced expression of various inflammatory-related genes, whose effects were abolished by EPL, whereas the inhibitory effects of ARB and TEM varied depending on the gene. Aldosterone caused greater accumulation of the oxidant stress marker 4-hydroxy-2-neonenal in the endothelium; its effect was abolished by EPL, ARB, or TEM. Aldosterone increased mRNA levels of reduced nicotinamide adenine dinucleotide phosphate oxidase components; their effect was abolished by EPL, whereas ARB and TEM decreased only the p47phox mRNA level but not that of p22phox or gp91phox. The present findings suggest that the Ang II-dependent pathway resulting from vascular angiotensin-converting enzyme up-regulation and Ang II-independent pathway are both involved in the underlying mechanisms resulting in the development of hypertension, vascular inflammation, and oxidative stress induced by aldosterone.

The role of the renin-angiotensin system and oxidative stress in spontaneously hypertensive rat mesenteric collateral growth impairment

2007 ◽  
Vol 292 (5) ◽  
pp. H2523-H2531 ◽  
Author(s):  
Steven J. Miller ◽  
Laura E. Norton ◽  
Michael P. Murphy ◽  
Michael C. Dalsing ◽  
Joseph L. Unthank
Keyword(s):  
Renin Angiotensin System ◽  
Ang Ii ◽  
Hypertensive Rats ◽  
Angiotensin System ◽  
Spontaneously Hypertensive ◽  
Renin Angiotensin ◽  
Growth Impairment ◽  
Collateral Growth ◽  
Collateral Artery

Recent clinical and animal studies have shown that collateral artery growth is impaired in the presence of vascular risk factors, including hypertension. Available evidence suggests that angiotensin-converting enzyme inhibitors (ACEI) promote collateral growth in both hypertensive humans and animals; however, the specific mechanisms are not established. This study evaluated the hypothesis that collateral growth impairment in hypertension is mediated by excess superoxide produced by NAD(P)H oxidase in response to stimulation of the ANG II type 1 receptor. After ileal artery ligation, mesenteric collateral growth did not occur in untreated, young, spontaneously hypertensive rats. Significant luminal expansion occurred in collaterals of spontaneously hypertensive rats treated with the superoxide dismutase mimetic tempol, the NAD(P)H oxidase inhibitor apocynin, and the ACEI captopril, but not ANG II type 1 (losartan) or type 2 (PD-123319) receptor blockers. The ACEI enalapril produced equivalent reduction of arterial pressure as captopril but did not promote luminal expansion. This suggests the effects of captopril on collateral growth might result from its antioxidant properties. RT-PCR demonstrated that ANG II type 1 receptor and angiotensinogen expression was reduced in collaterals of untreated rats. This local suppression of the renin angiotensin system provides a potential explanation for the lack of effect of enalapril and losartan on collateral growth. The results demonstrate the capability of antioxidant therapies, including captopril, to reverse impaired collateral artery growth and the novel finding that components of the local renin angiotensin system are naturally suppressed in collaterals.

scholarly journals Nicotine and the renin-angiotensin system

2018 ◽  
Vol 315 (5) ◽  
pp. R895-R906 ◽  
Author(s):  
Joshua M. Oakes ◽  
Robert M. Fuchs ◽  
Jason D. Gardner ◽  
Eric Lazartigues ◽  
Xinping Yue
Keyword(s):  
Cigarette Smoking ◽  
Renin Angiotensin System ◽  
Ang Ii ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Regulatory Systems ◽  
Health And Disease ◽  
Former Smokers ◽  
New Generation

Cigarette smoking is the single most important risk factor for the development of cardiovascular and pulmonary diseases (CVPD). Although cigarette smoking has been in constant decline since the 1950s, the introduction of e-cigarettes or electronic nicotine delivery systems 10 yr ago has attracted former smokers as well as a new generation of consumers. Nicotine is a highly addictive substance, and it is currently unclear whether e-cigarettes are “safer” than regular cigarettes or whether they have the potential to reverse the health benefits, notably on the cardiopulmonary system, acquired with the decline of tobacco smoking. Of great concern, nicotine inhalation devices are becoming popular among young adults and youths, emphasizing the need for awareness and further study of the potential cardiopulmonary risks of nicotine and associated products. This review focuses on the interaction between nicotine and the renin-angiotensin system (RAS), one of the most important regulatory systems on autonomic, cardiovascular, and pulmonary functions in both health and disease. The literature presented in this review strongly suggests that nicotine alters the homeostasis of the RAS by upregulating the detrimental angiotensin-converting enzyme (ACE)/angiotensin (ANG)-II/ANG II type 1 receptor axis and downregulating the compensatory ACE2/ANG-(1–7)/Mas receptor axis, contributing to the development of CVPD.

Splanchnic blood flow and hepatic glucose production in exercising humans: role of renin-angiotensin system

2001 ◽  
Vol 281 (6) ◽  
pp. R1854-R1861 ◽  
Author(s):  
Raynald Bergeron ◽  
Michael Kjær ◽  
Lene Simonsen ◽  
Jens Bülow ◽  
Dorthe Skovgaard ◽  
...  
Keyword(s):  
Blood Flow ◽  
Renin Angiotensin System ◽  
Glucose Production ◽  
Splanchnic Blood Flow ◽  
Control Group ◽  
Moderate Exercise ◽  
Ang Ii ◽  
Angiotensin System ◽  
Renin Angiotensin

The study examined the implication of the renin-angiotensin system (RAS) in regulation of splanchnic blood flow and glucose production in exercising humans. Subjects cycled for 40 min at 50% maximal O2 consumption (V˙o 2 max) followed by 30 min at 70% V˙o 2 maxeither with [angiotensin-converting enzyme (ACE) blockade] or without (control) administration of the ACE inhibitor enalapril (10 mg iv). Splanchnic blood flow was estimated by indocyanine green, and splanchnic substrate exchange was determined by the arteriohepatic venous difference. Exercise led to an ∼20-fold increase ( P < 0.001) in ANG II levels in the control group (5.4 ± 1.0 to 102.0 ± 25.1 pg/ml), whereas this response was blunted during ACE blockade (8.1 ± 1.2 to 13.2 ± 2.4 pg/ml) and in response to an orthostatic challenge performed postexercise. Apart from lactate and cortisol, which were higher in the ACE-blockade group vs. the control group, hormones, metabolites, V˙o 2, and RER followed the same pattern of changes in ACE-blockade and control groups during exercise. Splanchnic blood flow (at rest: 1.67 ± 0.12, ACE blockade; 1.59 ± 0.18 l/min, control) decreased during moderate exercise (0.78 ± 0.07, ACE blockade; 0.74 ± 0.14 l/min, control), whereas splanchnic glucose production (at rest: 0.50 ± 0.06, ACE blockade; 0.68 ± 0.10 mmol/min, control) increased during moderate exercise (1.97 ± 0.29, ACE blockade; 1.91 ± 0.41 mmol/min, control). Refuting a major role of the RAS for these responses, no differences in the pattern of change of splanchnic blood flow and splanchnic glucose production were observed during ACE blockade compared with controls. This study demonstrates that the normal increase in ANG II levels observed during prolonged exercise in humans does not play a major role in the regulation of splanchnic blood flow and glucose production.

scholarly journals Role of the renin-angiotensin system in the development of severe COVID-19 in hypertensive patients

2020 ◽  
Vol 319 (4) ◽  
pp. L596-L602
Author(s):  
Rodrigo Pacheco Silva-Aguiar ◽  
Diogo Barros Peruchetti ◽  
Patricia Rieken Macedo Rocco ◽  
Alvin H. Schmaier ◽  
Patrícia Machado Rodrigues e Silva ◽  
...  
Keyword(s):  
Critical Role ◽  
Renin Angiotensin System ◽  
Multiple Organ ◽  
Ang Ii ◽  
Angiotensin System ◽  
Hypertensive Patients ◽  
Renin Angiotensin ◽  
Therapeutic Benefits ◽  
Global Threat

A new form of severe acute respiratory syndrome (SARS) caused by SARS-coronavirus 2 (CoV-2), called COVID-19, has become a global threat in 2020. The mortality rate from COVID-19 is high in hypertensive patients, making this association especially dangerous. There appears to be a consensus, despite the lack of experimental data, that angiotensin II (ANG II) is linked to the pathogenesis of COVID-19. This process may occur due to acquired deficiency of angiotensin-converting enzyme 2 (ACE2), resulting in reduced degradation of ANG II. Furthermore, ANG II has a critical role in the genesis and worsening of hypertension. In this context, the idea that there is a surge in the level of ANG II with COVID-19 infection, causing multiple organ injuries in hypertensive patients becomes attractive. However, the role of other components of the renin angiotensin system (RAS) in this scenario requires elucidation. The identification of other RAS components in COVID-19 hypertension may provide both diagnostic and therapeutic benefits. Here, we summarize the pathophysiologic contributions of different components of RAS in hypertension and their possible correlation with poor outcome observed in hypertensive patients with COVID-19.

The role of local and systemic renin angiotensin system activation in a genetic model of sympathetic hyperactivity-induced heart failure in mice

2008 ◽  
Vol 294 (1) ◽  
pp. R26-R32 ◽  
Author(s):  
J. C. B. Ferreira ◽  
A. V. Bacurau ◽  
F. S. Evangelista ◽  
M. A. Coelho ◽  
E. M. Oliveira ◽  
...  
Keyword(s):  
Heart Failure ◽  
Renin Angiotensin System ◽  
Collagen Content ◽  
Ang Ii ◽  
Male Adult ◽  
Angiotensin System ◽  
Sympathetic Hyperactivity ◽  
Renin Angiotensin ◽  
Ras Activation

Sympathetic hyperactivity (SH) and renin angiotensin system (RAS) activation are commonly associated with heart failure (HF), even though the relative contribution of these factors to the cardiac derangement is less understood. The role of SH on RAS components and its consequences for the HF were investigated in mice lacking α2A and α2C adrenoceptor knockout (α2A/α2CARKO) that present SH with evidence of HF by 7 mo of age. Cardiac and systemic RAS components and plasma norepinephrine (PN) levels were evaluated in male adult mice at 3 and 7 mo of age. In addition, cardiac morphometric analysis, collagen content, exercise tolerance, and hemodynamic assessments were made. At 3 mo, α2A/α2CARKO mice showed no signs of HF, while displaying elevated PN, activation of local and systemic RAS components, and increased cardiomyocyte width (16%) compared with wild-type mice (WT). In contrast, at 7 mo, α2A/α2CARKO mice presented clear signs of HF accompanied only by cardiac activation of angiotensinogen and ANG II levels and increased collagen content (twofold). Consistent with this local activation of RAS, 8 wk of ANG II AT1 receptor blocker treatment restored cardiac structure and function comparable to the WT. Collectively, these data provide direct evidence that cardiac RAS activation plays a major role underlying the structural and functional abnormalities associated with a genetic SH-induced HF in mice.

scholarly journals Role of neurons and glia in the CNS actions of the renin-angiotensin system in cardiovascular control

2015 ◽  
Vol 309 (5) ◽  
pp. R444-R458 ◽  
Author(s):  
Annette D. de Kloet ◽  
Meng Liu ◽  
Vermalí Rodríguez ◽  
Eric G. Krause ◽  
Colin Sumners
Keyword(s):  
Blood Pressure ◽  
Glial Cell ◽  
Renin Angiotensin System ◽  
Cardiovascular Control ◽  
Health Concern ◽  
Ang Ii ◽  
Ongoing Research ◽  
Angiotensin System ◽  
Renin Angiotensin

Despite tremendous research efforts, hypertension remains an epidemic health concern, leading often to the development of cardiovascular disease. It is well established that in many instances, the brain plays an important role in the onset and progression of hypertension via activation of the sympathetic nervous system. Further, the activity of the renin-angiotensin system (RAS) and of glial cell-mediated proinflammatory processes have independently been linked to this neural control and are, as a consequence, both attractive targets for the development of antihypertensive therapeutics. Although it is clear that the predominant effector peptide of the RAS, ANG II, activates its type-1 receptor on neurons to mediate some of its hypertensive actions, additional nuances of this brain RAS control of blood pressure are constantly being uncovered. One of these complexities is that the RAS is now thought to impact cardiovascular control, in part, via facilitating a glial cell-dependent proinflammatory milieu within cardiovascular control centers. Another complexity is that the newly characterized antihypertensive limbs of the RAS are now recognized to, in many cases, antagonize the prohypertensive ANG II type 1 receptor (AT1R)-mediated effects. That being said, the mechanism by which the RAS, glia, and neurons interact to regulate blood pressure is an active area of ongoing research. Here, we review the current understanding of these interactions and present a hypothetical model of how these exchanges may ultimately regulate cardiovascular function.

scholarly journals The vascular renin-angiotensin system contributes to blunted vasodilation induced by transient high pressure in human adipose microvessels

2014 ◽  
Vol 307 (1) ◽  
pp. H25-H32 ◽  
Author(s):  
Matthew J. Durand ◽  
Shane A. Phillips ◽  
Michael E. Widlansky ◽  
Mary F. Otterson ◽  
David D. Gutterman
Keyword(s):  
Polyethylene Glycol ◽  
Enzyme Inhibitor ◽  
Renin Angiotensin System ◽  
Intraluminal Pressure ◽  
Ang Ii ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Pressure Sensitive ◽  
Endothelial Denudation

Increased intraluminal pressure can reduce endothelial function in resistance arterioles; however, the mechanism of this impairment is unknown. The purpose of this study was to determine the effect of local renin-angiotensin system inhibition on the pressure-induced blunting of endothelium-dependent vasodilation in human adipose arterioles. Arterioles (100–200 μm) were dissected from fresh adipose surgical specimens, cannulated onto glass micropipettes, pressurized to an intraluminal pressure of 60 mmHg, and constricted with endothelin-1. Vasodilation to ACh was assessed at 60 mmHg and again after a 30-min exposure to an intraluminal pressure of 150 mmHg. The vasodilator response to ACh was significantly reduced in vessels exposed to 150 mmHg. Exposure of the vessels to the superoxide scavenger polyethylene glycol-SOD (100 U/ml), the ANG II type 1 receptor antagonist losartan (10−6 mol/l), or the angiotensin-converting enzyme inhibitor captopril (10−5 mol/l) prevented the pressure-induced reduction in ACh-dependent vasodilation observed in untreated vessels. High intraluminal pressure had no effect on papaverine-induced vasodilation or ANG II sensitivity. Increased intraluminal pressure increased dihydroethidium fluorescence in cannulated vessels, which could be prevented by polyethylene glycol-SOD or losartan treatment and endothelial denudation. These data indicate that high intraluminal pressure can increase vascular superoxide and reduce nitric oxide-mediated vasodilation via activation of the vascular renin-angiotensin system. This study provides evidence showing that the local renin-angiotensin system in the human microvasculature may be pressure sensitive and contribute to endothelial dysfunction after acute bouts of hypertension.

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