Molecular inhibition of endoplasmic reticulum (ER) stress targeted to the subfornical organ (SFO) prevents slow‐pressor angiotensin‐II (Ang‐II) mediated hypertension

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.

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Endoplasmic reticulum stress is upstream of angiotensin‐II (Ang‐II)‐induced reactive oxygen species (ROS) formation in the subfornical organ (SFO)

The FASEB Journal ◽

10.1096/fasebj.27.1_supplement.906.15 ◽

2013 ◽

Vol 27 (S1) ◽

Author(s):

Colin N. Young ◽

Gang Wang ◽

Costantino Iadecola ◽

Allyn L. Mark ◽

Robin L. Davisson

Keyword(s):

Reactive Oxygen Species ◽

Endoplasmic Reticulum ◽

Angiotensin Ii ◽

Endoplasmic Reticulum Stress ◽

Reactive Oxygen ◽

Subfornical Organ ◽

Oxygen Species ◽

Ang Ii ◽

Ros Formation

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

Cells ◽

10.3390/cells9061327 ◽

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.

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

Frontiers in Physiology ◽

10.3389/fphys.2021.642752 ◽

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.

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NLRP3 Deletion Attenuated Angiotensin II-Induced Renal Fibrosis by Improving Mitochondrial Dysfunction and Endoplasmic Reticulum Stress

Nephron ◽

10.1159/000513739 ◽

2021 ◽

pp. 1-10

Author(s):

Yumei Zhang ◽

Yuqing Liu ◽

Xiao Bi ◽

Chun Hu ◽

Wei Ding

Keyword(s):

Endoplasmic Reticulum ◽

Angiotensin Ii ◽

Er Stress ◽

Mitochondrial Dysfunction ◽

Nlrp3 Inflammasome ◽

Renal Fibrosis ◽

Mitochondrial Morphology ◽

Ang Ii ◽

Wild Type ◽

Caspase 12

Background: Increasing evidence suggests that angiotensin II (Ang II), the bioactive pro-oxidant in the renin-angiotensin system, aggravates fibrosis, and the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is involved in multiple diseases, such as renal fibrosis. However, the role and underlying mechanism of Ang II in renal fibrosis remain unclear. Here, we investigated whether the NLRP3 inflammasome mediated Ang II-induced renal fibrosis, as well as the downstream pathways involved in this process. Methods: NLRP3−/− mice were used as a model to study Ang II-infused renal fibrosis. Mice were divided into 4 groups: sham wild type, Ang II-infused wild type, sham NLRP3−/−, and Ang II-infused NLRP3−/− groups. Ang II infusion-induced renal injury was confirmed by periodic acid-Schiff and Masson’s staining, immunohistochemistry, and transmission electron microscopy (TEM). Mitochondrial morphology was presented on TEM micrographs, and mitochondrial function was reflected by the protein levels of peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), mitochondrial transcription factor A (TFAM), dynamin-related protein 1 (DRP1), and mitofusin 2 (MFN2), as assessed by Western blotting. Endoplasmic reticulum (ER) stress was characterized by changes in the levels of ER chaperones, such as GRP94, BiP, CHOP, and caspase 12. Results: Ang II infusion increased cell proliferation, extracellular matrix overproduction, inflammatory cell infiltration, and glomerulosclerosis and induced obvious morphological abnormalities in podocytes. Ang II infusion promoted mitochondrial damage, as indicated by TEM, and induced mitochondrial dysfunction, as evidenced by downregulation of PGC-1α, TFAM, and increased mitochondrial ROS. In addition, DRP1 expression was upregulated, while MFN2 expression was markedly decreased. The levels of GRP94, BiP, CHOP, and caspase 12 were significantly increased. However, all these detrimental effects were attenuated by NLRP3 deletion. Conclusions: NLRP3 deletion may attenuate angiotensin II-induced renal fibrosis by improving mitochondrial dysfunction and ER stress.

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Abstract P118: Inhibition of Endoplasmic Reticulum Stress Prevents Intracranial Aneurysmal Rupture in a Mouse Model

Hypertension ◽

10.1161/hyp.70.suppl_1.p118 ◽

2017 ◽

Vol 70 (suppl_1) ◽

Author(s):

Daisuke Kudo ◽

Hajime Furukawa ◽

Satoru Eguchi ◽

Tomoki Hashimoto

Keyword(s):

Endoplasmic Reticulum ◽

Angiotensin Ii ◽

Mouse Model ◽

Er Stress ◽

Intracranial Aneurysms ◽

Vehicle Group ◽

Systemic Hypertension ◽

Aneurysmal Rupture ◽

Rupture Rate ◽

Salt Hypertension

Background: Aneurysmal subarachnoid hemorrhage (SAH) can cause significant mortality and morbidity. To develop a therapy for prevention of intracranial aneurysmal rupture and subsequent SAH, it is important to clarify the mechanism of intracranial aneurysmal rupture. Stimulation of the renin-angiotensin system (RAS) causes hypertension and cardiovascular remodeling. Recent evidence shows that angiotensin II enhances endoplasmic reticulum (ER) stress and inhibition of ER stress prevents angiotensin II-induced vascular remodeling but not hypertension in mice. RAS has also been implicated in intracranial aneurysms. We have previously shown that angiotensin II receptor blocker (losartan) prevented intracranial aneurysmal rupture in a mouse model without affecting systemic hypertension. To clarify the mechanism of intracranial aneurysmal rupture via RAS, we have tested our hypothesis that inhibition of ER stress prevents intracranial aneurysmal rupture in a mouse model. Method: We used a mouse model of intracranial aneurysms in which spontaneous aneurysmal rupture causes neurologic symptoms. Intracranial aneurysms were induced in wild type mice by a single stereotactic injection of elastase (35mU) into the cerebrospinal fluid at right basal cistern and deoxycorticosterone (DOCA)-salt hypertension. Vehicle or 4-phenylbutyric acid (PBA, ER stress inhibitor , 100mg/kg/day) was subcutaneously injected into all mice once a day. To detect aneurysmal rupture, we performed daily neurological examinations. Symptomatic mice were euthanized immediately when they developed neurological symptoms, and all asymptomatic mice were euthanized 21 days after aneurysm induction. The incidence of aneurysms and rupture rate were compared between vehicle group and PBA group. Results: The incidence of aneurysms was not significantly different between two groups (100% in vehicle, 20 of 20 vs. 87% in PBA, 20 of 23, p=0.09). However, rupture rate was significantly lower in the PBA group (60%, 12 of 20) than the vehicle group (95%, 19 of 20). (p=0.008). Conclusion: Inhibition of ER stress reduced aneurysmal rupture in a mouse model of intracranial aneurysm induced by combination of elastase injection and DOCA-salt hypertension.

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Ablation of subfornical organ does not prevent angiotensin-induced water drinking in sheep

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1986.250.6.r1052 ◽

1986 ◽

Vol 250 (6) ◽

pp. R1052-R1059 ◽

Cited By ~ 3

Author(s):

M. J. McKinley ◽

D. A. Denton ◽

R. G. Park ◽

R. S. Weisinger

Keyword(s):

Angiotensin Ii ◽

Hypertonic Saline ◽

Water Deprivation ◽

Subfornical Organ ◽

Ang Ii ◽

Water Drinking

The subfornical organ (SFO) and surrounding periventricular tissue were ablated in sheep. Such a lesion did not significantly reduce water drinking in response to intracarotid, intravenous, or intracerebroventricular infusions of [Val5]angiotensin II amide (ANG II) but caused reduced intake of water in response to intracarotid infusion of hypertonic saline. The dipsogenic response of these sheep to water deprivation for 3 days was similar to that of normal sheep subjected to water deprivation. Although the results are not conclusive in excluding the SFO from having a role in ANG II-induced drinking, they show that there are receptors outside the SFO sensitive to blood-borne ANG II that are involved in water drinking in sheep. The results also show that tissue in the SFO or its surroundings may be involved in drinking caused by acute hypertonicity.

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Enalapril decreases angiotensin II receptors in subfornical organ of SHR

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1989.256.6.h1609 ◽

1989 ◽

Vol 256 (6) ◽

pp. H1609-H1614 ◽

Cited By ~ 3

Author(s):

A. J. Nazarali ◽

J. S. Gutkind ◽

F. M. Correa ◽

J. M. Saavedra

Keyword(s):

Angiotensin Ii ◽

Angiotensin Converting Enzyme ◽

Enzyme Inhibitor ◽

Area Postrema ◽

Subfornical Organ ◽

Ang Ii ◽

Converting Enzyme ◽

Converting Enzyme Inhibitors ◽

Wky Rats ◽

Enalapril Treatment

We studied brain angiotensin II (ANG II) receptors by quantitative autoradiography in adult normotensive Wistar-Kyoto (WKY) rats and in spontaneously hypertensive rats (SHR) after treating the rats with the converting-enzyme inhibitor enalapril, 25 mg/kg, po daily for 14 days. Enalapril treatment decreased blood pressure in only SHR, inhibited plasma angiotensin-converting enzyme activity by 85%, and increased plasma ANG I concentration and renin activity in both WKY and SHR. In the untreated SHR animals, ANG II receptor concentrations were higher in the subfornical organ, the area postrema, the nucleus of the solitary tract, and the inferior olive when compared with the untreated WKY rats. Enalapril treatment produced a large decrease in only subfornical organ ANG II receptors of SHR. The selective reversal of the alteration in subfornical organ ANG II receptors in SHR may indicate a decreased central response to ANG II and may be related to the mode of action of angiotensin-converting enzyme inhibitors in this model.

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mTORC1 Signaling Contributes to Drinking But Not Blood Pressure Responses to Brain Angiotensin II

Endocrinology ◽

10.1210/en.2016-1243 ◽

2016 ◽

Vol 157 (8) ◽

pp. 3140-3148 ◽

Cited By ~ 4

Author(s):

Kenjiro Muta ◽

Donald A. Morgan ◽

Justin L. Grobe ◽

Curt D. Sigmund ◽

Kamal Rahmouni

Keyword(s):

Angiotensin Ii ◽

Water Intake ◽

Drinking Behavior ◽

Subfornical Organ ◽

Dependent Manner ◽

Ang Ii ◽

Mtorc1 Signaling ◽

Wide Range ◽

The Brain

Mechanistic target of rapamycin complex 1 (mTORC1) is a molecular node that couples extracellular cues to a wide range of cellular events controlling various physiological processes. Here, we identified mTORC1 signaling as a critical mediator of angiotensin II (Ang II) action in the brain. In neuronal GT1–7 cells, we show that Ang II stimulates neuronal mTORC1 signaling in an Ang II type 1 receptor-dependent manner. In mice, a single intracerebroventricular (ICV) injection or chronic sc infusion of Ang II activated mTORC1 signaling in the subfornical organ, a critical brain region in cardiovascular control and fluid balance. Moreover, transgenic sRA mice with brain-specific overproduction of Ang II displayed increased mTORC1 signaling in the subfornical organ. To test the functional role of brain mTORC1 in mediating the action of Ang II, we examined the consequence of mTORC1 inhibition with rapamycin on Ang II-induced increase in water intake and arterial pressure. ICV pretreatment with rapamycin blocked ICV Ang II-mediated increases in the frequency, duration, and amount of water intake but did not interfere with the pressor response evoked by Ang II. In addition, ICV delivery of rapamycin significantly reduced polydipsia, but not hypertension, of sRA mice. These results demonstrate that mTORC1 is a novel downstream pathway of Ang II type 1 receptor signaling in the brain and selectively mediates the effect of Ang II on drinking behavior.

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