scholarly journals Long-Term Angiotensin II Infusion Induces Oxidative and Endoplasmic Reticulum Stress and Modulates Na+ Transporters Through the Nephron

2021 ◽  
Vol 12 ◽  
Author(s):  
Bruna Bezerra Lins ◽  
Fernando Augusto Malavazzi Casare ◽  
Flávia Ferreira Fontenele ◽  
Guilherme Lopes Gonçalves ◽  
Maria Oliveira-Souza
Keyword(s):  
Oxidative Stress ◽  
Endoplasmic Reticulum ◽  
Angiotensin Ii ◽  
Protein Expression ◽  
Er Stress ◽  
Mrna Expression ◽  
Kidney Diseases ◽  
Kidney Tissue ◽  
Ang Ii ◽  
Gene And Protein Expression

High plasma angiotensin II (Ang II) levels are related to many diseases, including hypertension, and chronic kidney diseases (CKDs). Here, we investigated the relationship among prolonged Ang II infusion/AT1 receptor (AT1R) activation, oxidative stress, and endoplasmic reticulum (ER) stress in kidney tissue. In addition, we explored the chronic effects of Ang II on tubular Na+ transport mechanisms. Male Wistar rats were subjected to sham surgery as a control or prolonged Ang II treatment (200 ng⋅kg–1⋅min–1, 42 days) with or without losartan (10 mg⋅kg–1⋅day–1) for 14 days. Ang II/AT1R induced hypertension with a systolic blood pressure of 173.0 ± 20 mmHg (mmHg, n = 9) compared with 108.0 ± 7 mmHg (mmHg, n = 7) in sham animals. Under these conditions, gene and protein expression levels were evaluated. Prolonged Ang II administration/AT1R activation induced oxidative stress and ER stress with increased Nox2, Nox4, Cyba and Ncf1 mRNA expression, phosphorylated PERK and eIF2α protein expression as well as Atf4 mRNA expression. Ang II/AT1R also raised Il1b, Nfkb1 and Acta2 mRNA expression, suggesting proinflammatory, and profibrotic effects. Regarding Na+ tubular handling, Ang II/AT1R enhanced cortical non-phosphorylated and phospho/S552/NHE3, NHE1, ENaC β, NKCC2, and NCC protein expression. Our results also highlight the therapeutic potential of losartan, which goes beyond the antihypertensive effect, playing an important role in kidney tissue. This treatment reduced oxidative stress and ER stress signals and recovered relevant parameters of the maintenance of renal function, preventing the progression of Ang II-induced CKD.

scholarly journals Endoplasmic reticulum and oxidant stress mediate nuclear factor-κB activation in the subfornical organ during angiotensin II hypertension

2015 ◽  
Vol 308 (10) ◽  
pp. C803-C812 ◽  
Author(s):  
Colin N. Young ◽  
Anfei Li ◽  
Frederick N. Dong ◽  
Julie A. Horwath ◽  
Catharine G. Clark ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Endoplasmic Reticulum ◽  
Transcription Factor ◽  
Angiotensin Ii ◽  
Er Stress ◽  
Bioluminescence Imaging ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Ang Ii ◽  
Arterial Blood

Endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) generation in the brain circumventricular subfornical organ (SFO) mediate the central hypertensive actions of Angiotensin II (ANG II). However, the downstream signaling events remain unclear. Here we tested the hypothesis that angiotensin type 1a receptors (AT1aR), ER stress, and ROS induce activation of the transcription factor nuclear factor-κB (NF-κB) during ANG II-dependent hypertension. To spatiotemporally track NF-κB activity in the SFO throughout the development of ANG II-dependent hypertension, we used SFO-targeted adenoviral delivery and longitudinal bioluminescence imaging in mice. During low-dose infusion of ANG II, bioluminescence imaging revealed a prehypertensive surge in NF-κB activity in the SFO at a time point prior to a significant rise in arterial blood pressure. SFO-targeted ablation of AT1aR, inhibition of ER stress, or adenoviral scavenging of ROS in the SFO prevented the ANG II-induced increase in SFO NF-κB. These findings highlight the utility of bioluminescence imaging to longitudinally track transcription factor activation during the development of ANG II-dependent hypertension and reveal an AT1aR-, ER stress-, and ROS-dependent prehypertensive surge in NF-κB activity in the SFO. Furthermore, the increase in NF-κB activity before a rise in arterial blood pressure suggests a causal role for SFO NF-κB in the development of ANG II-dependent hypertension.

scholarly journals Structural Characterization and Antioxidant Activity of Polysaccharides from Athyrium multidentatum (Doll.) Ching in d-Galactose-Induced Aging Mice via PI3K/AKT Pathway

Molecules ◽  
2019 ◽  
Vol 24 (18) ◽  
pp. 3364 ◽  
Author(s):  
Liang Jing ◽  
Jing-Ru Jiang ◽  
Dong-Mei Liu ◽  
Ji-Wen Sheng ◽  
Wei-Fen Zhang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Molecular Weight ◽  
Protein Expression ◽  
Mrna Expression ◽  
Caspase 3 ◽  
Akt Pathway ◽  
Protective Mechanism ◽  
Related Factor ◽  
Bax Protein ◽  
Gene And Protein Expression

The purpose of this study was to characterize the polysaccharides from Athyrium multidentatum (Doll.) Ching (AMC) rhizome and explore the protective mechanism against d-galactose-induced oxidative stress in aging mice. Methods: A series of experiments, including molecular weight, monosaccharide composition, Fourier transform infrared (FT-IR) spectroscopy, and 1H nuclear magnetic resonance (1H NMR) spectroscopy were carried out to characterize AMC polysaccharides. The mechanism was investigated exploring d-galactose-induced aging mouse model. Quantitative real-time reverse transcription polymerase chain reaction (RT-qPCR) and western blotting assays were performed to assess the gene and protein expression in liver. Key findings: Our results showed that AMC polysaccharides were mainly composed of mannose (Man), rhamnose (Rha), glucuronic acid (Glc A), glucose (Glc), galactose (Gal), arabinose (Ara), and fucose (Fuc) in a molar ratio of 0.077:0.088:0.09:1:0.375:0.354:0.04 with a molecular weight of 33203 Da (Mw). AMC polysaccharides strikingly reversed d-galactose-induced changes in mice, including upregulated phosphatidylinositol 3-kinase (PI3K), Akt, nuclear factor-erythroid 2-related factor 2 (Nrf2), forkhead box O3a (FOXO3a), and hemeoxygenase-1 (HO-1) mRNA expression, raised Bcl-2/Bax ratio, downregulated caspase-3 mRNA expression, enhanced Akt, phosphorylation of Akt (p-Akt), Nrf2 and HO-1 protein expression, decreased caspase-3, and Bax protein expression. Conclusion: AMC polysaccharides attenuated d-galactose-induced oxidative stress and cell apoptosis by activating the PI3K/AKT pathway, which might in part contributed to their anti-aging activity.

Kinin B1 receptor upregulation by angiotensin II and endothelin-1 in rat vascular smooth muscle cells: receptors and mechanisms

2010 ◽  
Vol 299 (5) ◽  
pp. H1625-H1632 ◽  
Author(s):  
Marielle Morand-Contant ◽  
Madhu B. Anand-Srivastava ◽  
Réjean Couture
Keyword(s):  
Oxidative Stress ◽  
Smooth Muscle ◽  
Angiotensin Ii ◽  
Vascular Smooth Muscle ◽  
Protein Expression ◽  
Smooth Muscle Cells ◽  
Receptor Antagonist ◽  
Vascular Smooth Muscle Cells ◽  
Ang Ii ◽  
Phosphatidylinositol 3 Kinase

Oxidative stress upregulates the kinin B1 receptor (B1R) in diabetes and hypertension. Since angiotensin II (ANG II) and endothelin-1 (ET-1) are increased in these disorders, this study aims at determining the role of these two prooxidative peptides in B1R expression in rat vascular smooth muscle cells (VSMC). In the A10 cell line and aortic VSMC, ANG II enhanced B1R protein expression in a concentration- and time-dependent manner (maximal at 1 μM and 6 h). In A10 cells, ANG II (1 μM) also increased B1R mRNA expression at 3 h and the activation of induced B1R with the agonist [Sar-d-Phe8]-des-Arg9-BK (10 nM, 5 min) significantly enhanced mitogen -activated protein kinase (MAPK1/2) phosphorylation. The enhancing effect of ANG II on B1R protein expression in A10 cells was normalized by the AT1 (losartan) but not by the AT2 (PD123319) receptor antagonist. Furthermore, it was inhibited by inhibitors of phosphatidylinositol 3-kinase (wortmannin) and NF-κB (MG132) but not of MAPK (PD098059). Whereas the ETB receptor antagonist (BQ788) had no effect, the ETA receptor antagonist (BQ123) blocked the effect of ANG II at 6–8 h but not at an early time point. BQ123 and BQ788 also blocked the increasing effect of ET-1 on B1R protein expression. Antioxidants ( N-acetyl-l-cysteine and diphenyleneiodonium) abolished ANG II- and ET-1-increased B1R protein expression. In conclusion, B1R induction is linked to oxidative stress and activation of phosphatidylinositol 3-kinase and NF-κB. The newly synthesized B1R is functional and can activate MAPK signaling in VSMC. The effect of ANG II is mediated by the AT1 receptor and the subsequent activation of ETA through ET-1 release.

scholarly journals The Interplay of Mitochondrial Oxidative Stress and Endoplasmic Reticulum Stress in Cardiovascular Fibrosis in Obese Rats

Antioxidants ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1274
Author(s):  
Francisco V. Souza-Neto ◽  
Sara Jiménez-González ◽  
Beatriz Delgado-Valero ◽  
Raquel Jurado-López ◽  
Marie Genty ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Control Diet ◽  
Ang Ii ◽  
Mitochondrial Oxidative Stress ◽  
Relevant Role ◽  
Male Wistar Rats ◽  
Cardiovascular Fibrosis ◽  
Stress Activation

We have evaluated the role of mitochondrial oxidative stress and its association with endoplasmic reticulum (ER) stress activation in the progression of obesity-related cardiovascular fibrosis. MitoQ (200 µM) was orally administered for 7 weeks to male Wistar rats that were fed a high-fat diet (HFD, 35% fat) or a control diet (CT, 3.5% fat). Obese animals presented cardiovascular fibrosis accompanied by increased levels of extracellular matrix proteins and profibrotic mediators. These alterations were associated with ER stress activation characterized by enhanced levels (in heart and aorta vs. CT group, respectively) of immunoglobulin binding protein (BiP; 2.1-and 2.6-fold, respectively), protein disulfide-isomerase A6 (PDIA6; 1.9-fold) and CCAAT-enhancer-binding homologous protein (CHOP; 1.5- and 1.8-fold, respectively). MitoQ treatment was able to prevent (p < 0.05) these modifications at cardiac and aortic levels. MitoQ (5 nM) and the ER stress inhibitor, 4-phenyl butyric acid (4 µM), were able to block the prooxidant and profibrotic effects of angiotensin II (Ang II, 10−6 M) in cardiac and vascular cells. Therefore, the data show a crosstalk between mitochondrial oxidative stress and ER stress activation, which mediates the development of cardiovascular fibrosis in the context of obesity and in which Ang II can play a relevant role.

P0979BENEFICIAL EFFECT OF CHLOROQUINE AND AMODIAQUINE ON DIABETIC TUBULOPATHY BY ATTENUATING MITOCHONDRIAL NOX4 AND ENDOPLASMIC RETICULUM STRESS

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
So-Young Lee ◽  
Dong Ho Yang ◽  
Yu Ho Lee ◽  
Mi Jung Lee ◽  
Hyung-Jong Kim ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Protein Expression ◽  
Er Stress ◽  
High Glucose ◽  
Kidney Tissue ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Diabetic Mice ◽  
Chronic Hyperglycemia ◽  
Inflammatory Protein ◽  
Diabetic Tubulopathy

Abstract Background and Aims Oxidative stress induced by chronic hyperglycemia is recognized as a significant mechanistic contributor to the development of diabetic kidney disease (DKD). Nonphagocytic nicotinamide adenine dinucleotide phosphate oxidase 4 (Nox4) is a major source of reactive oxygen species (ROS) in many cell types and in the kidney tissue of diabetic animals. We designed this study to explore the therapeutic potential of chloroquine and amodiaquine for inhibiting mitochondrial Nox4 and diabetic tubular injury. Method Human renal proximal tubular epithelial cells (hRPTCs) were cultured in high-glucose media (30 mM D-glucose), and diabetes was induced with streptozotocin (STZ, 50 mg/kg i.p. for 5 days) in male C57/BL6J mice. Chloroquine and amodiaquine were administered to the mice via intraperitoneal injection for 14 weeks. Results Chloroquine and amodiaquine inhibited mitochondrial Nox4 and increased mitochondrial mass in hRPTCs under high-glucose conditions. Reduced mitochondrial ROS production after treatment with the drugs resulted in decreased endoplasmic reticulum (ER) stress, suppressed inflammatory protein expression and reduced cell apoptosis in hRPTCs under high-glucose conditions. Notably, chloroquine and amodiaquine treatment diminished Nox4 activation and ER stress in the kidneys of STZ-induced diabetic mice. In addition, we observed attenuated inflammatory protein expression and albuminuria in STZ-induced diabetic mice after chloroquine and amodiaquine treatment. Conclusion We substantiated the protective actions of chloroquine and amodiaquine in diabetic tubulopathy associated with reduced mitochondrial Nox4 activation and ER stress alleviation. Further studies exploring the roles of mitochondrial Nox4 in the pathogenesis of DKD could suggest new therapeutic targets for patients with DKD. Figure None

scholarly journals Role of microRNA 690 in Mediating Angiotensin II Effects on Inflammation and Endoplasmic Reticulum Stress

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1327
Author(s):  
Kalhara R. Menikdiwela ◽  
Latha Ramalingam ◽  
Mostafa M. Abbas ◽  
Halima Bensmail ◽  
Shane Scoggin ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Adipose Tissue ◽  
Angiotensin Ii ◽  
Er Stress ◽  
Mitogen Activated Protein Kinase ◽  
Luciferase Reporter ◽  
Small Rna Sequencing ◽  
Ang Ii ◽  
Protective Function

Overactivation of the renin–angiotensin system (RAS) during obesity disrupts adipocyte metabolic homeostasis and induces endoplasmic reticulum (ER) stress and inflammation; however, underlying mechanisms are not well known. We propose that overexpression of angiotensinogen (Agt), the precursor protein of RAS in adipose tissue or treatment of adipocytes with Angiotensin II (Ang II), RAS bioactive hormone, alters specific microRNAs (miRNA), that target ER stress and inflammation leading to adipocyte dysfunction. Epididymal white adipose tissue (WAT) from B6 wild type (Wt) and transgenic male mice overexpressing Agt (Agt-Tg) in adipose tissue and adipocytes treated with Ang II were used. Small RNA sequencing and microarray in WAT identified differentially expressed miRNAs and genes, out of which miR-690 and mitogen-activated protein kinase kinase 3 (MAP2K3) were validated as significantly up- and down-regulated, respectively, in Agt-Tg, and in Ang II-treated adipocytes compared to respective controls. Additionally, the direct regulatory role of miR-690 on MAP2K3 was confirmed using mimic, inhibitors and dual-luciferase reporter assay. Downstream protein targets of MAP2K3 which include p38, NF-κB, IL-6 and CHOP were all reduced. These results indicate a critical post-transcriptional role for miR-690 in inflammation and ER stress. In conclusion, miR-690 plays a protective function and could be a useful target to reduce obesity.

scholarly journals Collecting duct (pro)renin receptor targets ENaC to mediate angiotensin II-induced hypertension

2017 ◽  
Vol 312 (2) ◽  
pp. F245-F253 ◽  
Author(s):  
Kexin Peng ◽  
Xiaohan Lu ◽  
Fei Wang ◽  
Adam Nau ◽  
Ren Chen ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Protein Expression ◽  
Mrna Expression ◽  
Collecting Duct ◽  
Underlying Mechanism ◽  
Ang Ii ◽  
Induced Hypertension ◽  
Mrna And Protein Expression ◽  
Receptor Targets

The (pro)renin receptor (PRR) is abundantly expressed in the collecting duct (CD) and the expression is further induced by angiotensin II (ANG II). The present study was conducted to investigate the role of CD PRR during ANG II-induced hypertension and to further explore the underlying mechanism. Radiotelemetry demonstrated that a 1-wk ANG II infusion gradually and significantly induced hypertensive response in floxed mice and this response was significantly attenuated in mice lacking PRR in the CD (termed CD PRR KO). ANG II infusion in floxed mice increased urinary renin activity and selectively induced renal medullary α-epithelial sodium channel (α-ENaC) mRNA and protein expression, all of which were blunted in the null mice. In cultured mpkCCD cells grown in Transwells, transepithelial Na+ transport as measured by using a volt-ohmmeter was transiently stimulated by acute ANG II treatment, which was abolished by a PRR antagonist, PRO20. In a chronic setting, ANG II treatment induced α-ENaC mRNA expression in mpkCCD cells, which was similarly blocked by PRO20. Chronic intramedullary infusion of an ENaC inhibitor amiloride in rats significantly attenuated ANG II-induced hypertension. Overall, the present study suggests that CD PRR contributes to ANG II-induced hypertension at least partially via activation of renal medullary ENaC.

Abstract 097: EGF Receptor And ER Stress Mediate End-organ Damage But Not Hypertension Induced By Angiotensin II In Mice

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Katherine J Elliott ◽  
Toshiyuki Tsuji ◽  
Takashi Obama ◽  
Takehiko Takayanagi ◽  
Steven Forrester ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Er Stress ◽  
Egf Receptor ◽  
Organ Damage ◽  
Ang Ii ◽  
End Organ Damage ◽  
Egfr Activation ◽  
And Oxidative Stress

In cultured vascular smooth muscle cells (VSMC), a metalloprotease ADAM17-dependent EGF receptor (EGFR) activation mediates ERK1/2 activation and subsequent hypertrophy induced by angiotensin II (Ang II). Both ER and oxidative stress are implicated in hypertensive end-organ damage. We hypothesized that pharmacological inhibition of EGFR may prevent end-organ damage but not hypertension in mice infused with Ang II via suppression of ER/oxidative stress. To test this hypothesis, we have evaluated Ang II-induced end-organ damage as well as hypertension in C57Bl/6 mice with or without an EGFR inhibitor erlotinib (20mg/kg/day ip) or ER stress inhibitor 4-phenyl butyric acid (PBA: 1g/kg/day in drinking water). Upon Ang II infusion (1000 ng/kg/min) for 2 weeks, control mice showed phenotypes of cardiac hypertrophy including increased HW/BW ratio (mg/g: 7.9±0.7 vs 5.7±0.6 p<0.01 n=8) and increased LVPWd assessed by cardiac echo (mm: 0.98±0.14 vs 0.69±0.05, p<0.05 n=8) compared with saline infusion. Histological assessments demonstrated medial hypertrophy and perivascular fibrosis of coronary arteries with Ang II infusion. In contrast, cardiac hypertrophy and vascular remodeling were attenuated in mice with Ang II plus erlotinib or PBA; HW/BW ratio (6.8±0.6 or 6.2±0.6 n=8), and cardiac echo (LVPWd: 0.65±0.07 or 0.80±0.07 n=8) compared with saline infusion. Renal fibrosis observed with Ang II infusion was also attenuated in mice with Ang II plus erotinib or PBA. However, Ang II induced similar levels of hypertension in non-treated, erlotinib-treated or PBA-treated mice assessed by telemetry (MAP mmHg: 144±9 vs 149±20 or 139±4). Ang II infusion in mice enhanced ADAM17 and phospho-Tyr EGFR staining in vasculatures of heart and kidney, whereas mice with Ang II plus erlotinib or PBA had diminished phospho-Tyr EGFR staining and no ADAM17 staining in the vasculatures. In addition, IHC analyses revealed less oxidative stress and less ER stress in heart and kidney of Ang II-infused mice with erlotinib or PBA. These data suggest that EGFR activation and subsequent ER stress enhancement are critical for end organ damage via induction of ADAM17 and oxidative stress and is independent from blood pressure regulation.

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