Abstract 612: ACE2-Independent Sex Differences In Oxidative Stress

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Jan Wysocki ◽  
Karla Evora ◽  
Moody Salem ◽  
Christoph Maier ◽  
Minghao Ye ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Sex Differences ◽  
Nadph Oxidase ◽  
Total Protein ◽  
Oxidase Activity ◽  
Kidney Injury ◽  
Ang Ii ◽  
Male Mice ◽  
Nadph Oxidase Activity ◽  
Female Mice

Many of the pathophysiological effects of angiotensin II (Ang II) are attributed to its stimulation of NADPH oxidases and the consequent production of reactive oxygen species. Female sex has generally lower cardiovascular morbidity and is also less susceptible to kidney injury than males. The basis of these phenomena is not well understood but it is possible that sex-differential regulation of oxidative stress through activation of the RAS and its key effector, Ang II, plays an important contributor role. Here we hypothesized that Ang II levels are higher in male mice and that this is associated with sex-differences in kidney levels of ACE2, an Ang II-degrading enzyme abundantly expressed in the kidney. Parameters of oxidative stress such as, NADPH oxidase activity and malondialdehyde levels (MDA) were measured in kidneys from female and age-matched male C57BL6 mice. At 40 weeks of age, NADPH oxidase activity (p<0.01) and MDA levels (p<0.05) were significantly lower in female than in male mice. Female mice had lower kidney levels of the pro-oxidant peptide, Ang II (0.94±0.19 vs. 1.66±0.17 fmol/mg total protein, p<0.05, respectively). The difference in kidney Ang II levels between females and males was also observed in the face of complete ACE2 genetic deficiency (1.08±0.16 vs 1.97±0.25 fmol/mg total protein, p<0.05, respectively). Consistent with kidney Ang II levels, urinary Ang II levels measured in urines from female WT mice were also significantly lower than in male WT mice (23.6±2.2 vs. 47.9±8.8 pg/mg creatinine, p<0.05) despite significantly higher levels of urinary ACE2 activity in male mice as compared to female mice (7.0±0.5 vs. 3.6±0.3, p<0.01, respectively). Female mice have lower basal levels of kidney oxidative stress than males and exhibit lower levels of kidney and urinary Ang II. The mechanism involved in sex differences in the levels of kidney and urine Ang II does not appear to depend on ACE2.

Abstract 1380: Antioxidants Decrease Neuronal Angiotensin II Type 1 Receptor in Heart Failure: Inhibition of Activator Protein 1 and Jun N-Terminal Kinase

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Dongmei Liu ◽  
Lie Gao ◽  
Kurtis G Cornish ◽  
Irving H Zucker
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Angiotensin Ii ◽  
Nadph Oxidase ◽  
Oxidase Activity ◽  
Neuronal Cell ◽  
Activator Protein 1 ◽  
Ang Ii ◽  
Nadph Oxidase Activity ◽  
Activator Protein

In a previous study, we showed that Ang II type I receptor (AT1R) expression increased in the rostral ventrolateral medulla (RVLM) of chronic heart failure (CHF) rabbits and in normal rabbits infused with intracerebroventricular (ICV) Angiotensin II (AngII). The present study investigated if oxidative stress plays a role in Ang II induced AT1R upregulation and its relationship to the transcription factor activator protein 1 (AP1) in CHF rabbits and in the CATHa neuronal cell line. In neuronal cell cultures, Ang II significantly increased AT1R mRNA by 153 ± 22%, P <0.01; c-Jun mRNA by 90 ± 10%, P < 0.01; NADPH oxidase activity by 126 ± 43%, P < 0.01 versus untreated cells; Tempol, Apocynin and the AP 1 inhibitor Tanshinone II reversed the increased AT1R, c-Jun expression and NADPH oxidase activity induced by AngII. We examined the effect of ICV Tempol on expression of these proteins in the RVLM of CHF rabbits. Compared to untreated CHF rabbits Tempol significantly decreased AT1R protein expression (0.88±0.16 vs. 1.6±0.29, P <0.05), phosphorylated Jnk protein (0.10±0.02 vs. 0.31±0.10, P <0.05), and phosphorylated c-Jun (0.02±0.001 vs. 0.14±0.05, P <0.05). These data suggest that Ang II induces AT1R upregulation at the transcriptional level by activation of oxidative stress and AP1 in both cultured cells and in intact brain. Antioxidant agents may be beneficial in CHF by decreasing AT1R expression through the Jnk and AP1 pathway.

scholarly journals Effect of renin inhibition and AT1R blockade on myocardial remodeling in the transgenic Ren2 rat

2008 ◽  
Vol 295 (1) ◽  
pp. E103-E109 ◽  
Author(s):  
Adam Whaley-Connell ◽  
Javad Habibi ◽  
Shawna A. Cooper ◽  
Vincent G. DeMarco ◽  
Melvin R. Hayden ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Blood Pressure ◽  
Nadph Oxidase ◽  
Oxidase Activity ◽  
Myocardial Remodeling ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Nadph Oxidase Activity ◽  
Renin Inhibition

Angiotensin II (Ang II) stimulation of the Ang type 1 receptor (AT1R) facilitates myocardial remodeling through NADPH oxidase-mediated generation of oxidative stress. Components of the renin-angiotensin system constitute an autocrine/paracrine unit in the myocardium, including renin, which is the rate-limiting step in the generation of Ang II. This investigation sought to determine whether cardiac oxidative stress and cellular remodeling could be attenuated by in vivo renin inhibition and/or AT1R blockade in a rodent model of chronically elevated tissue Ang II levels, the transgenic (mRen2)27 rat (Ren2). The Ren2 overexpresses the mouse renin transgene with resultant hypertension, insulin resistance, and cardiovascular damage. Young (6- to 7-wk-old) heterozygous (+/−) male Ren2 and age-matched Sprague-Dawley rats were treated with the renin inhibitor aliskiren, which has high preferential affinity for human and mouse renin, an AT1R blocker, irbesartan, or placebo for 3 wk. Myocardial NADPH oxidase activity and immunostaining for NADPH oxidase subunits and 3-nitrotyrosine were evaluated and remodeling changes assessed by light and transmission electron microscopy. Blood pressure, myocardial NADPH oxidase activity and subunit immunostaining, 3-nitrotyrosine, perivascular fibrosis, mitochondrial content, and markers of activity were significantly increased in Ren2 compared with SD littermates. Both renin inhibition and blockade of the AT1R significantly attenuated cardiac functional and structural alterations, although irbesartan treatment resulted in greater reductions of both blood pressure and markers of oxidative stress. Collectively, these data suggest that both reduce changes driven, in part, by Ang II-mediated increases in NADPH oxidase and, in part, increases in blood pressure.

scholarly journals AT1 receptor-mediated augmentation of angiotensinogen, oxidative stress, and inflammation in ANG II-salt hypertension

2012 ◽  
Vol 302 (1) ◽  
pp. F85-F94 ◽  
Author(s):  
Lucienne S. Lara ◽  
Michael McCormack ◽  
Laura C. Semprum-Prieto ◽  
Sylvia Shenouda ◽  
Dewan S. A. Majid ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Proliferation ◽  
Nadph Oxidase ◽  
Oxidase Activity ◽  
Tissue Injury ◽  
Collagen Deposition ◽  
Ang Ii ◽  
Mesangial Expansion ◽  
Nadph Oxidase Activity ◽  
Salt Hypertension

Augmentation of intrarenal angiotensinogen (AGT) synthesis, secretion, and excretion is associated with the development of hypertension, renal oxidative stress, and tissue injury during ANG II-dependent hypertension. High salt (HS) exacerbates hypertension and kidney injury, but the mechanisms remain unclear. In this study, we determined the consequences of HS intake alone compared with chronic ANG II infusion and combined HS plus ANG II on the stimulation of urinary AGT (uAGT), renal oxidative stress, and renal injury markers. Sprague-Dawley rats were subjected to 1) a normal-salt diet [NS, n = 5]; 2) HS diet [8% NaCl, n = 5]; 3) ANG II infusion in NS rats [ANG II 80 ng/min, n = 5]; 4) ANG II infusion in HS rats [ANG II+HS, n = 5]; and 5) ANG II infusion in HS rats treated with ANG II type 1 receptor blocker (ARB) [ANG II+HS+ARB, n = 5] for 14 days. Rats fed a HS diet alone did not show changes in systolic blood pressure (SBP), proteinuria, cell proliferation, or uAGT excretion although they did exhibit mesangial expansion, collagen deposition, and had increased NADPH oxidase activity accompanied by increased peroxynitrite formation in the kidneys. Compared with ANG II rats, the combination of ANG II infusion and a HS diet led to exacerbation in SBP (175 ± 10 vs. 221 ± 8 mmHg; P < 0.05), proteinuria (46 ± 7 vs. 127 ± 7 mg/day; P < 0.05), and uAGT (1,109 ± 70 vs.. 7,200 ± 614 ng/day; P < 0.05) associated with greater collagen deposition, mesangial expansion, interstitial cell proliferation, and macrophage infiltration. In both ANG II groups, the O2− levels were increased due to increased NADPH oxidase activity without concomitant increases in peroxynitrite formation. The responses in ANG II rats were prevented or ameliorated by ARB treatment. The results indicate that HS independently stimulates ROS formation, which may synergize with the effect of ANG II to limit peroxynitrite formation, leading to exacerbation of uAGT and greater injury during ANG II salt hypertension.

scholarly journals Neuroprotective Benefits of Exercise and MitoQ on Memory Function, Mitochondrial Dynamics, Oxidative Stress, and Neuroinflammation in D-Galactose-Induced Aging Rats

2021 ◽  
Vol 11 (2) ◽  
pp. 164
Author(s):  
Jae-Hoon Jeong ◽  
Jung-Hoon Koo ◽  
Jang Soo Yook ◽  
Joon-Yong Cho ◽  
Eun-Bum Kang
Keyword(s):  
Oxidative Stress ◽  
Antioxidant Activity ◽  
Cognitive Impairment ◽  
Nadph Oxidase ◽  
Learning And Memory ◽  
Oxidase Activity ◽  
Mitochondrial Dynamics ◽  
Nadph Oxidase Activity ◽  
Aging Rats ◽  
Positive Effects

Exercise and antioxidants have health benefits that improve cognitive impairment and may act synergistically. In this study, we examined the effects of treadmill exercise (TE) and mitochondria-targeted antioxidant mitoquinone (MitoQ), individually or combined, on learning and memory, mitochondrial dynamics, NADPH oxidase activity, and neuroinflammation and antioxidant activity in the hippocampus of D-galactose-induced aging rats. TE alone and TE combined with MitoQ in aging rats reduced mitochondrial fission factors (Drp1, Fis1) and increased mitochondrial fusion factors (Mfn1, Mfn2, Opa1). These groups also exhibited improved NADPH oxidase activity and antioxidant activity (SOD-2, catalase). TE or MitoQ alone decreased neuroinflammatory response (COX-2, TNF-α), but the suppression was greater with their combination. In addition, aging-increased neuroinflammation in the dentate gyrus was decreased in TE but not MitoQ treatment. Learning and memory tests showed that, contrarily, MitoQ alone demonstrated some similar effects to TE but not a definitive improvement. In conclusion, this study demonstrated that MitoQ exerted some positive effects on aging when used as an isolated treatment, but TE had a more effective role on cognitive impairment, oxidative stress, inflammation, and mitochondria dysfunction. Our findings suggest that the combination of TE and MitoQ exerted no synergistic effects and indicated regular exercise should be the first priority in neuroprotection of age-related cognitive decline.

scholarly journals Attenuation of renal excretory responses to ANG II during inhibition of superoxide dismutase in anesthetized rats

2010 ◽  
Vol 298 (2) ◽  
pp. F401-F407 ◽  
Author(s):  
Md. Abdul Hye Khan ◽  
Mohammed Toriqul Islam ◽  
Alexander Castillo ◽  
Dewan Syed Abdul Majid
Keyword(s):  
Superoxide Dismutase ◽  
Nadph Oxidase ◽  
Oxidase Activity ◽  
Ang Ii ◽  
Sod Activity ◽  
Doppler Flowmetry ◽  
Nadph Oxidase Activity ◽  
Blood Flows ◽  
Renal Responses

To examine the functional interaction between superoxide dismutase (SOD) and NADPH oxidase activity, we assessed renal responses to acute intra-arterial infusion of ANG II (0.5 ng·kg−1·min−1) before and during administration of a SOD inhibitor, diethyldithiocarbamate (DETC, 0.5 mg·kg−1·min−1), in enalaprilat-pretreated (33 μg·kg−1·min−1) rats ( n = 11). Total (RBF) and regional (cortical, CBF; medullary; MBF) renal blood flows were determined by Transonic and laser-Doppler flowmetry, respectively. Renal cortical and medullary tissue NADPH oxidase activity in vitro was determined using the lucigenin-chemiluminescence method. DETC treatment alone resulted in decreases in RBF, CBF, MBF, glomerular filtration rate (GFR), urine flow (V), and sodium excretion (UNaV) as reported previously. Before DETC, ANG II infusion decreased RBF (−18 ± 3%), CBF (−16 ± 3%), MBF [−5 ± 6%; P = not significant (NS)], GFR (−31 ± 4%), V (−34 ± 2%), and UNaV (−53 ± 3%). During DETC infusion, ANG II also caused similar reductions in RBF (−20 ± 4%), CBF (−19 ± 3%), MBF (−2 ± 2; P = NS), and in GFR (−22 ± 7%), whereas renal excretory responses (V; −12 ± 2%; UNaV; −24 ± 4%) were significantly attenuated compared with those before DETC. In in vitro experiments, ANG II (100 μM) enhanced NADPH oxidase activity both in cortical [13,194 ± 1,651 vs. 20,914 ± 2,769 relative light units (RLU)/mg protein] and in medullary (21,296 ± 2,244 vs. 30,597 ± 4,250 RLU/mg protein) tissue. Application of DETC (1 mM) reduced the basal levels and prevented ANG II-induced increases in NADPH oxidase activity in both tissues. These results demonstrate that renal excretory responses to acute ANG II administration are attenuated during SOD inhibition, which seems related to a downregulation of NADPH oxidase in the deficient condition of SOD activity.

scholarly journals Protective Role of Endogenous Kallistatin in Vascular Injury and Senescence by Inhibiting Oxidative Stress and Inflammation

2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
Julie Chao ◽  
Youming Guo ◽  
Lee Chao
Keyword(s):  
Oxidative Stress ◽  
Endothelial Cells ◽  
Nadph Oxidase ◽  
Vascular Injury ◽  
Oxidase Activity ◽  
Sirtuin 1 ◽  
Mouse Lung ◽  
Heparin Binding ◽  
Diabetic Mice ◽  
Nadph Oxidase Activity

Kallistatin was identified in human plasma as a tissue kallikrein-binding protein and a serine proteinase inhibitor. Kallistatin exerts pleiotropic effects on angiogenesis, oxidative stress, inflammation, apoptosis, fibrosis, and tumor growth. Kallistatin levels are markedly reduced in patients with coronary artery disease, sepsis, diabetic retinopathy, inflammatory bowel disease, pneumonia, and cancer. Moreover, plasma kallistatin levels are positively associated with leukocyte telomere length in young African Americans, indicating the involvement of kallistatin in aging. In addition, kallistatin treatment promotes vascular repair by increasing the migration and function of endothelial progenitor cells (EPCs). Kallistatin via its heparin-binding site antagonizes TNF-α-induced senescence and superoxide formation, while kallistatin’s active site is essential for inhibiting miR-34a synthesis, thus elevating sirtuin 1 (SIRT1)/eNOS synthesis in EPCs. Kallistatin inhibits oxidative stress-induced cellular senescence by upregulating Let-7g synthesis, leading to modulate Let-7g-mediated miR-34a-SIRT1-eNOS signaling pathway in human endothelial cells. Exogenous kallistatin administration attenuates vascular injury and senescence in association with increased SIRT1 and eNOS levels and reduced miR-34a synthesis and NADPH oxidase activity, as well as TNF-α and ICAM-1 expression in the aortas of streptozotocin- (STZ-) induced diabetic mice. Conversely, endothelial-specific depletion of kallistatin aggravates vascular senescence, oxidative stress, and inflammation, with further reduction of Let-7g, SIRT1, and eNOS and elevation of miR-34a in mouse lung endothelial cells. Furthermore, systemic depletion of kallistatin exacerbates aortic injury, senescence, NADPH oxidase activity, and inflammatory gene expression in STZ-induced diabetic mice. These findings indicate that endogenous kallistatin displays a novel role in protection against vascular injury and senescence by inhibiting oxidative stress and inflammation.

Thioredoxin-1/peroxiredoxin-1 as sensors of oxidative stress mediated by NADPH oxidase activity in atherosclerosis

2015 ◽  
Vol 86 ◽  
pp. 352-361 ◽  
Author(s):  
Julio Madrigal-Matute ◽  
Carlos-Ernesto Fernandez-Garcia ◽  
Luis Miguel Blanco-Colio ◽  
Elena Burillo ◽  
Ana Fortuño ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nadph Oxidase ◽  
Oxidase Activity ◽  
Nadph Oxidase Activity ◽  
Peroxiredoxin 1 ◽  
Thioredoxin 1

scholarly journals Erythrocyte NADPH oxidase activity modulated by Rac GTPases, PKC, and plasma cytokines contributes to oxidative stress in sickle cell disease

Blood ◽  
2013 ◽  
Vol 121 (11) ◽  
pp. 2099-2107 ◽  
Author(s):  
Alex George ◽  
Suvarnamala Pushkaran ◽  
Diamantis G. Konstantinidis ◽  
Sebastian Koochaki ◽  
Punam Malik ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Sickle Cell Disease ◽  
Nadph Oxidase ◽  
Oxidase Activity ◽  
Ros Production ◽  
Cell Disease ◽  
Nadph Oxidase Activity ◽  
Rac Gtpases ◽  
Key Points ◽  
Plasma Cytokines

Key Points Sickle RBC ROS production is mediated in part by NADPH oxidase activity. Sickle RBC ROS production can be induced by plasma signaling molecules.

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.

scholarly journals The Post-Ischemic Increase in GluA2 Ser880 Phosphorylation Involves NADPH Oxidase

2018 ◽  
Vol 4 (1) ◽  
pp. 170-181
Author(s):  
Darrell A. Jackson ◽  
Fanny Astruc-Diaz ◽  
Nicole M. Byrnes ◽  
Phillip H. Beske
Keyword(s):  
Oxidative Stress ◽  
Nadph Oxidase ◽  
Oxidase Activity ◽  
Hippocampal Slices ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Glucose Deprivation ◽  
Subunit Composition ◽  
Stress Signaling ◽  
Scaffolding Proteins ◽  
Nadph Oxidase Activity

Most 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl) propanoic acid receptors (AMPARs) expressed on adult hippocampal pyramidal neurons contain the edited form of GluA2 (Q607R) and are thus impermeable to Ca2+/Zn2+ entry.  Following ischemic injury, these receptors undergo a subunit composition change, switching from a GluA2-containing Ca2+/Zn2+-impermeable AMPAR to a GluA2-lacking Ca2+/Zn2+-permeable AMPAR. Recent studies indicate that an oxidative stress signaling pathway is responsible for the I/R-induced changes in AMPAR subunit composition.  Studies suggest that nicotinamide adenine dinucleotide phosphate-oxidase (NADPH oxidase), a superoxide generator, is the source that initiates the oxidative stress-signaling cascade during post-ischemic reperfusion. The objective of the present study was to determine if suppression of NADPH oxidase activity prevents the increase in phosphorylation and subsequent internalization of the GluA2 AMPAR subunit during reperfusion of post-ischemic hippocampal slices. In this study, we demonstrated that exposure of adult rat hippocampal slices to oxygen glucose deprivation/reperfusion (OGD/R) results in an increase in Ser880 phosphorylation of the GluA2 subunit.  The increase in Ser880 phosphorylation resulted in the dissociation of GluA2 from the scaffolding proteins Glutamate receptor-interacting protein 1 (GRIP1) and AMPAR binding protein (ABP), thus enabling the association of GluA2 with protein interacting with C kinase 1 (PICK1). OGD/R also resulted in an increase in the association of activated protein kinase C ? (PKC?) with PICK1. We have found that pharmacological inhibition of NADPH oxidase with apocynin diminishes the OGD/R-induced increase in activated PKC? association with PICK1 and subsequent Ser880 phosphorylation of GluA2. Suppression of NADPH oxidase activity also blunted OGD/R-induced decreased association of GluA2 with the scaffolding proteins GRIP1 and ABP.  Protein phosphatase 2A (PP2A), which regulates PKC? activity by dephosphorylating the kinase, was inactivated by OGD/R-induced increase in tyrosine phosphorylation of the phosphatase (Y307). Inhibition of NADPH oxidase activity ameliorated OGD/R-induced PP2A phosphorylation and inactivation. Our findings are consistent with a model of OGD/R-induced Ser880 phosphorylation of GluA2 that implicates NADPH oxidase mediated inactivation of PP2A and sustained PKC? phosphorylation of GluA2.

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