Exaggerated vasomotor response to ANG II in rats with fetal programming of hypertension associated with exposure to a low-protein diet during gestation

2006 ◽  
Vol 291 (4) ◽  
pp. R1060-R1068 ◽  
Author(s):  
C. Yzydorczyk ◽  
F. Gobeil ◽  
G. Cambonie ◽  
I. Lahaie ◽  
N. L. O. Lê ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Renin Angiotensin System ◽  
Underlying Mechanism ◽  
Maximal Response ◽  
Ang Ii ◽  
Vasomotor Response ◽  
Enhanced Chemiluminescence ◽  
Low Protein ◽  
Diphenylene Iodonium ◽  
Nadph Oxidase Complex

The renin-angiotensin system plays a key role in the initiation and maintenance of elevated blood pressure associated with altered intrauterine milieu. The current studies were undertaken to verify whether vascular response to ANG II is increased in adult offspring of low-protein fed dams (LP) compared with control (CTRL) and if so, to examine underlying mechanism(s). ANG II-induced contraction of carotid rings was increased in LP (Emax, the maximum asymptote of the curve, relative to maximal response to KCl 80 mM: 230 ± 3% LP vs. 201 ± 2% CTRL, P < 0.05). In both groups, contraction to ANG II was mediated solely by AT1R. Responses to thromboxane A2 analog U-46619 and to KCl 80 mM under step increases in tension were similar between groups. Endothelium depletion enhanced contraction to ANG II in both groups, more so in LP. Blockade of endothelin formation had no effect on response to ANG II, and ANG-(1–7) did not elicit vasomotor response in either group. Superoxide dismutase (SOD) analog Tempol normalized LP without modifying CTRL response to ANG II. Basal levels of superoxide (aortic segments, lucigenin-enhanced chemiluminescence and fluorescent dye hydroethidine) were higher in LP. ANG II further increased superoxide production in LP only, and this was inhibited by coincubation with diphenylene iodonium or apocynin (inhibitor of NADPH oxidase complex). AT1R expression in carotid arteries was increased in LP, whereas SOD expression was unchanged. In conclusion, vasoconstriction to ANG II is exaggerated in this model of developmental programming of hypertension, secondary to enhanced vascular production of superoxide anion by NADPH oxidase with concomitant increase of AT1R expression.

scholarly journals ACE2 Shedding and the Role in COVID-19

2022 ◽  
Vol 11 ◽  
Author(s):  
Jieqiong Wang ◽  
Huiying Zhao ◽  
Youzhong An
Keyword(s):  
Amino Acids ◽  
Viral Entry ◽  
Kidney Injury ◽  
Renin Angiotensin System ◽  
Underlying Mechanism ◽  
Ang Ii ◽  
Converting Enzyme ◽  
Angiotensin System ◽  
Angiotensin Converting Enzyme 2 ◽  
Transmembrane Glycoprotein

Angiotensin converting enzyme 2 (ACE2), a transmembrane glycoprotein, is an important part of the renin-angiotensin system (RAS). In the COVID-19 epidemic, it was found to be the receptor of severe acute respiratory syndrome coronavirus 2 (SARS-COV-2). ACE2 maintains homeostasis by inhibiting the Ang II-AT1R axis and activating the Ang I (1-7)-MasR axis, protecting against lung, heart and kidney injury. In addition, ACE2 helps transport amino acids across the membrane. ACE2 sheds from the membrane, producing soluble ACE2 (sACE2). Previous studies have pointed out that sACE2 plays a role in the pathology of the disease, but the underlying mechanism is not yet clear. Recent studies have confirmed that sACE2 can also act as the receptor of SARS-COV-2, mediating viral entry into the cell and then spreading to the infective area. Elevated concentrations of sACE2 are more related to disease. Recombinant human ACE2, an exogenous soluble ACE2, can be used to supplement endogenous ACE2. It may represent a potent COVID-19 treatment in the future. However, the specific administration concentration needs to be further investigated.

scholarly journals Human glomerular endothelium: interplay among glucose, free fatty acids, angiotensin II, and oxidative stress

2010 ◽  
Vol 298 (1) ◽  
pp. F125-F132 ◽  
Author(s):  
Edgar A. Jaimes ◽  
Ping Hua ◽  
Run-Xia Tian ◽  
Leopoldo Raij
Keyword(s):  
Fatty Acids ◽  
Endothelial Cells ◽  
Angiotensin Ii ◽  
Nadph Oxidase ◽  
Free Fatty Acids ◽  
High Glucose ◽  
Renin Angiotensin System ◽  
Macrovascular Disease ◽  
Ang Ii ◽  
Cox 2

Glomerular endothelial cells (GEC) are strategically situated within the capillary loop and adjacent to the glomerular mesangium. GEC serve as targets of metabolic, biochemical, and hemodynamic signals that regulate the glomerular microcirculation. Unequivocally, hyperglycemia, hypertension, and the local renin-angiotensin system partake in the initiation and progression of diabetic nephropathy (DN). Whether free fatty acids (FFA) and reactive oxygen species (ROS) that have been associated with the endothelial dysfunction of diabetic macrovascular disease also contribute to DN is not known. Since endothelial cells from different organs and from different species may display different phenotypes, we employed human GEC to investigate the effect of high glucose (22.5 mmol/l), FFA (800 μmol/l), and angiotensin II (ANG II; 10−7 mol/l) on the genesis of ROS and their effects on endothelial nitric oxide synthase (eNOS), cyclooxygenase-2 (COX-2), and the synthesis of prostaglandins (PGs). We demonstrated that high glucose but not high FFA increased the expression of a dysfunctional eNOS as well as increased ROS from NADPH oxidase (100%) and likely from uncoupled eNOS. ANG II also induced ROS from NADPH oxidase. High glucose and ANG II upregulated (100%) COX-2 via ROS and significantly increased the synthesis of prostacyclin (PGI2) by 300%. In contrast, FFA did not upregulate COX-2 but increased PGI2 (500%). These novel studies are the first in human GEC that characterize the differential role of FFA, hyperglycemia, and ANG II on the genesis of ROS, COX-2, and PGs and their interplay in the early stages of hyperglcyemia.

scholarly journals Enhanced sensitivity to acute angiotensin II is testosterone dependent in adult male growth-restricted offspring

2010 ◽  
Vol 298 (5) ◽  
pp. R1421-R1427 ◽  
Author(s):  
Norma B. Ojeda ◽  
Thomas P. Royals ◽  
Joshua T. Black ◽  
John Henry Dasinger ◽  
Jeremy M. Johnson ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Adult Male ◽  
Pressor Response ◽  
Renin Angiotensin System ◽  
Plasma Renin ◽  
Underlying Mechanism ◽  
Male Rats ◽  
Ang Ii ◽  
Enhanced Sensitivity ◽  
And Control

Placental insufficiency results in intrauterine growth restriction (IUGR) and hypertension in adult male growth-restricted rats. Although renal ANG II and plasma renin activity do not differ between growth-restricted and control rats, blockade of the renin-angiotensin system (RAS) abolishes hypertension in growth-restricted rats, suggesting that the RAS contributes to IUGR-induced hypertension. Moreover, castration abolishes hypertension in growth-restricted rats, indicating an important role for testosterone. Therefore, we hypothesized that enhanced responsiveness to ANG II contributes to hypertension in this model of IUGR and that androgens may play a pivotal role in this enhanced response. Physiological parameters were determined at 16 wk of age in male rats pretreated with enalapril (40 mg·kg−1·day−1) for 1 wk. Baseline blood pressures were similar between growth-restricted (112 ± 3 mmHg) and control (110 ± 2 mmHg) rats; however, an enhanced pressor response to acute ANG II (100 ng·kg−1·min−1 for 30 min) was observed in growth-restricted (160 ± 2 mmHg) vs. control (136 ± 2 mmHg; P < 0.05) rats. Castration abolished the enhanced pressor response to acute ANG II in growth-restricted (130 ± 2 mmHg) rats with no significant effect on blood pressure in controls (130 ± 2 mmHg). Blood pressure was increased to a similar extent above baseline in response to acute phenylephrine (100 μg/min) in control (184 ± 5 mmHg) and growth-restricted (184 ± 8 mmHg) rats, suggesting the enhanced pressor response in growth-restricted rats is ANG II specific. Thus, these results suggest that growth-restricted rats exhibit an enhanced responsiveness to ANG II that is testosterone dependent and indicate that the RAS may serve as an underlying mechanism in mediating hypertension programmed in response to IUGR.

scholarly journals Renin Inhibition Attenuates Insulin Resistance, Oxidative Stress, and Pancreatic Remodeling in the Transgenic Ren2 Rat

Endocrinology ◽  
2008 ◽  
Vol 149 (11) ◽  
pp. 5643-5653 ◽  
Author(s):  
Javad Habibi ◽  
Adam Whaley-Connell ◽  
Melvin R. Hayden ◽  
Vincent G. DeMarco ◽  
Rebecca Schneider ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Reactive Oxygen Species ◽  
Nadph Oxidase ◽  
Oxidase Activity ◽  
Renin Angiotensin System ◽  
Oxygen Species ◽  
Ang Ii ◽  
Angiotensin System ◽  
Nadph Oxidase Activity ◽  
Renin Inhibition

Emerging evidence indicates that pancreatic tissue expresses all components of the renin-angiotensin system. However, the functional role is not well understood. This investigation examined renin inhibition on pancreas structure/function in the transgenic Ren2 rat harboring the mouse renin gene, a model of tissue renin overexpression. Renin is the rate-limiting step in the generation of angiotensin II (Ang II), which stimulates the generation of reactive oxygen species in a variety of tissues. Overexpression of renin in Ren2 rats results in hypertension, insulin resistance, and cardiovascular and renal damage. Young (6–7 wk old) insulin-resistant male Ren2 and age-matched insulin sensitive Sprague Dawley rats were treated with the renin inhibitor, aliskiren (50 mg/kg·d by ip injection), or placebo for 21 d. At 21 d, the Ren2 demonstrated insulin resistance with increased islet insulin, Ang II, and reduced total insulin receptor substrate (IRS)-1, IRS-2, and Akt immunostaining. There was increased islet nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and subunits (p47phox and Rac1) as well as increased nitrotyrosine immunostaining (each P &lt; 0.05). These functional abnormalities were associated with a disordered islet architecture; increased islet-exocrine interface, pericapillary fibrosis, and structurally abnormal mitochondria and content in endocrine and exocrine pancreas. In vivo treatment with aliskiren normalized systemic insulin resistance and islet insulin, Ang II, NADPH oxidase activity/subunits, and nitrotyrosine and improved total IRS-1 and Akt phosphorylation (each P &lt; 0.05) as well as islet/exocrine structural abnormalities. Collectively, these data suggest that pancreatic functional/structural changes are driven, in part, by tissue renin-angiotensin system-mediated increases in NADPH oxidase and reactive oxygen species generation, abnormalities attenuated with direct renin inhibition.

Up-regulation of renal renin–angiotensin system and inflammatory mechanisms in the prenatal programming by low-protein diet: beneficial effect of the post-weaning losartan treatment

2018 ◽  
Vol 9 (5) ◽  
pp. 530-535 ◽  
Author(s):  
I. K. M. Watanabe ◽  
Z. P. Jara ◽  
R. A. Volpini ◽  
M. d. C. Franco ◽  
F. F. Jung ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Renin Angiotensin System ◽  
Protein Diet ◽  
Low Protein Diet ◽  
Oxygen Species ◽  
Ang Ii ◽  
Prenatal Programming ◽  
Angiotensin System ◽  
Low Protein ◽  
Losartan Treatment

AbstractPrevious studies have shown that the renin–angiotensin system (RAS) is affected by adverse maternal nutrition during pregnancy. The aim of this study was to investigate the effects of a maternal low-protein diet on proinflammatory cytokines, reactive oxygen species and RAS components in kidney samples isolated from adult male offspring. We hypothesized that post-weaning losartan treatment would have beneficial effects on RAS activity and inflammatory and oxidative stress markers in these animals. Pregnant Sprague–Dawley rats were fed with a control (20% casein) or low-protein diet (LP) (6% casein) throughout gestation. After weaning, the LP pups were randomly assigned to LP and LP-losartan groups (AT1 receptor blockade: 10 mg/kg/day until 20 weeks of age). At 20 weeks of age, blood pressure levels were higher and renal RAS was activated in the LP group. We also observed several adverse effects in the kidneys of the LP group, including a higher number of CD3, CD68 and proliferating cell nuclear antigen-positive cells and higher levels of collagen and reactive oxygen species in the kidney. Further, our results revealed that post-weaning losartan treatment completely abolished immune cell infiltration and intrarenal RAS activation in the kidneys of LP rats. The prevention of augmentation of angiotensin (Ang II) concentration abolished inflammatory and fibrotic events, indicating that Ang II via the AT1 receptor is essential for pathological initiation. Our results suggest that the prenatal programming of hypertension is dependent on the up-regulation of local RAS and presence of immune cells in the kidney.

Interleukin-10 counteracts impaired endothelium-dependent relaxation induced by ANG II in murine aortic rings

2007 ◽  
Vol 292 (6) ◽  
pp. H3103-H3108 ◽  
Author(s):  
Saiprasad M. Zemse ◽  
Rob H. P. Hilgers ◽  
R. Clinton Webb
Keyword(s):  
Nadph Oxidase ◽  
Inflammatory Cytokine ◽  
Immunohistochemical Analysis ◽  
Interleukin 10 ◽  
Oxidase Inhibitor ◽  
Maximal Response ◽  
Ang Ii ◽  
A Subunit ◽  
Anti Inflammatory ◽  
Anti Inflammatory Cytokine

ANG II stimulates the production of reactive oxygen species and activates proinflammatory cytokines leading to endothelial dysfunction. We hypothesized that the anti-inflammatory cytokine IL-10 counteracts the impairment in endothelium-dependent ACh relaxation caused by ANG II. Aortic rings of C57BL/6 mice were incubated in DMEM in the presence of vehicle (deionized H2O), ANG II (100 nmol/l), recombinant mouse IL-10 (300 ng/ml), or both ANG II and IL-10 for 22 h at 37°C. After incubation, rings were mounted in a wire myograph to assess endothelium-dependent vasorelaxation to cumulative concentrations of ACh. Overnight exposure of aortic rings to ANG II resulted in blunted ACh-induced vasorelaxation compared with that shown in untreated rings (maximal response = 44 ± 3% vs. 64 ± 3%, respectively; P < 0.05). IL-10 treatment significantly restored this impairment in relaxation (63 ± 2%). In addition, the NADPH oxidase inhibitor apocynin restored the impairment in relaxation (maximal response = 76 ± 3%). Western blotting showed increased gp91 phox expression (a subunit of NADPH oxidase) in response to ANG II. Vessels treated with a combination of ANG II and IL-10 showed decreased expression of gp91 phox. Immunohistochemical analysis showed increased gp91 phox expression in ANG II-treated vessels compared with those treated with combined ANG II and IL-10. We found that the anti-inflammatory cytokine IL-10 prevents impairment in endothelium-dependent vasorelaxation in response to long-term incubation with ANG II via decreasing NADPH oxidase expression.

scholarly journals Differences in oxidative stress status and expression of MKP-1 in dorsal medulla of transgenic rats with altered brain renin-angiotensin system

2012 ◽  
Vol 303 (8) ◽  
pp. R799-R806 ◽  
Author(s):  
Manisha Nautiyal ◽  
Prasad V. G. Katakam ◽  
David W. Busija ◽  
Patricia E. Gallagher ◽  
E. Ann Tallant ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nadph Oxidase ◽  
Renin Angiotensin System ◽  
Ang Ii ◽  
Transgenic Rats ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Sd Rats ◽  
Medullary Tissue ◽  
Oxidative Stress Status

ANG II-stimulated production of reactive oxygen species (ROS) through NADPH oxidase is suggested to activate MAPK pathways, which are implicated in neurally mediated pressor effects of ANG II. Emerging evidence suggests that ANG-(1–7) up regulates MAPK phosphatases to reduce MAPK signaling and attenuate actions of ANG II. Whether angiotensin peptides participate in long-term regulation of these systems in the brain is not known. Therefore, we determined tissue and mitochondrial ROS, as well as expression and activity of MAPK phosphatase-1 (MKP-1) in brain dorsal medullary tissue of hypertensive transgenic (mRen2)27 rats exhibiting higher ANG II/ANG-(1–7) tone or hypotensive transgenic rats with targeted decreased glial expression of angiotensinogen, ASrAOGEN (AS) exhibiting lower ANG II/ANG-(1–7) tone compared with normotensive Sprague-Dawley (SD) rats that serve as the control strain. Transgenic (mRen2)27 rats showed higher medullary tissue NADPH oxidase activity and dihydroethidium fluorescence in isolated mitochondria vs. SD or AS rats. Mitochondrial uncoupling protein 2 was lower in AS and unchanged in (mRen2)27 compared with SD rats. MKP-1 mRNA and protein expression were higher in AS and unchanged in (mRen2)27 compared with SD rats. AS rats also had lower phosphorylated ERK1/2 and JNK consistent with higher MKP-1 activity. Thus, an altered brain renin-angiotensin system influences oxidative stress status and regulates MKP-1 expression. However, there is a dissociation between these effects and the hemodynamic profiles. Higher ROS was associated with hypertension in (mRen2)27 and normal MKP-1, whereas the higher MKP-1 was associated with hypotension in AS, where ROS was normal relative to SD rats.

Blockade of AT1 receptor partially restores vasoreactivity, NOS expression, and superoxide levels in cerebral and carotid arteries of hindlimb unweighting rats

2009 ◽  
Vol 106 (1) ◽  
pp. 251-258 ◽  
Author(s):  
Ran Zhang ◽  
Yun-Gang Bai ◽  
Le-Jian Lin ◽  
Jun-Xiang Bao ◽  
Yu-Yang Zhang ◽  
...  
Keyword(s):  
Vascular Reactivity ◽  
Carotid Arteries ◽  
Cerebral Arteries ◽  
Renin Angiotensin System ◽  
Maximal Response ◽  
Ang Ii ◽  
Hindlimb Unweighting ◽  
Basilar Arteries ◽  
Receptor Signaling Pathway ◽  
Oxide Synthase

Previous studies have demonstrated activation of the local renin-angiotensin system in hindlimb unweighting (HU) rat vasculature. The present study intended to identify the effects of blockade of angiotensin II (ANG II) type 1 (AT1) receptors with losartan on vascular reactivity, nitric oxide synthase (NOS) expression, and superoxide anion (O2•−) levels in 3-wk HU rat cerebral and carotid arteries. Three weeks later, vasoconstriction, vasodilatation, endothelial NOS (eNOS) and inducible NOS (iNOS) protein, as well as O2•− levels in rat cerebral and carotid arteries were examined. We found that HU enhanced maximal response to KCl/5-hydroxytryptamine ( P < 0.01) in basilar arteries and KCl/phenylephrine ( P < 0.05) in common carotid arteries from HU rats. Acetylcholine induced concentration-dependent vasodilatation in all the artery rings, but with significantly smaller amplitude in basilar ( P < 0.01) and common carotid ( P < 0.05) arteries from HU rats than those from control rats. Chronic treatment with losartan partially restored response to vasoconstrictors and acetylcholine-induced vasodilatation in basilar ( P < 0.01) and common carotid ( P < 0.05) arteries from losartan-treated HU rats. Furthermore, iNOS content in cerebral arteries and eNOS/iNOS content in carotid arteries were significantly ( P < 0.01) increased in HU rats. Meanwhile, HU increased O2•− levels in all the layers of these arteries. However, losartan restored NOS content and O2•− levels toward normal. These results suggested that the HU-induced enhancement of vasoconstriction and reduction in endothelium-dependent relaxation involved alterations in O2•− and NOS content through an ANG II/AT1 receptor signaling pathway.

scholarly journals Maternal high-fat diet acts on the brain to induce baroreflex dysfunction and sensitization of angiotensin II-induced hypertension in adult offspring

2018 ◽  
Vol 314 (5) ◽  
pp. H1061-H1069 ◽  
Author(s):  
Yu-Ping Zhang ◽  
Yan-Li Huo ◽  
Zhi-Qin Fang ◽  
Xue-Fang Wang ◽  
Jian-Dong Li ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Proinflammatory Cytokines ◽  
High Fat Diet ◽  
Control Diet ◽  
Renin Angiotensin System ◽  
Adult Offspring ◽  
Ang Ii ◽  
High Fat ◽  
Pressor Responses ◽  
The Brain

Accumulating evidence indicates that maternal high-fat diet (HFD) is associated with metabolic syndrome and cardiovascular disease in adult offspring. The present study tested the hypothesis that maternal HFD modulates the brain renin-angiotensin system (RAS), oxidative stress, and proinflammatory cytokines that alter angiotensin II (ANG II) and TNF-α actions and sensitize the ANG II-elicited hypertensive response in adult offspring. All offspring were cross fostered by dams on the same or opposite diet to yield the following four groups: offspring from normal-fat control diet-fed dams suckled by control diet-fed dams (OCC group) or by HFD-fed dams (OCH group) and offspring from HFD-fed dams fed a HFD suckled by control diet-fed dams (OHC group) or by HFD-fed dams (OHH group). RT-PCR analyses of the lamina terminalis and paraventricular nucleus indicated upregulation of mRNA expression of several RAS components, NADPH oxidase, and proinflammatory cytokines in 10-wk-old male offspring of dams fed a HFD during either pregnancy, lactation, or both (OHC, OCH, and OHH groups). These offspring also showed decreased cardiac baroreflex sensitivity and increased pressor responses to intracerebroventricular microinjection of either ANG II or TNF-α. Furthermore, chronic systemic infusion of ANG II resulted in enhanced upregulation of mRNA expression of RAS components, NADPH oxidase, and proinflammatory cytokines in the lamina terminalis and paraventricular nucleus and an augmented hypertensive response in the OHC, OCH, and OHH groups compared with the OCC group. The results suggest that maternal HFD blunts cardiac baroreflex function and enhances pressor responses to ANG II or proinflammatory cytokines through upregulation of the brain RAS, oxidative stress, and inflammation. NEW & NOTEWORTHY The results of our study indicate that a maternal high-fat diet during either pregnancy or lactation is sufficient for perinatal programming of sensitization for hypertension, which is associated with hyperreactivity of central cardiovascular nuclei that, in all likelihood, involves elevated expression of the renin-angiotensin system, NADPH oxidase, and proinflammatory cytokines. The present study demonstrates, for the first time, the central mechanism underlying maternal high-fat diet sensitization of the hypertensive response in adult offspring.

Sign in / Sign up

Export Citation Format

Share Document