PVN Blockade of p44/42 MAPK Pathway Attenuates Salt-induced Hypertension through Modulating Neurotransmitters and Attenuating Oxidative Stress

Gao, Hong-Li; Yu, Xiao-Jing; Liu, Kaili; Shi, Xiao-Lian; Qi, Jie; Chen, Yanmei; Zhang, Yan; Bai, Juan; Yi, Qiu-Yue; Feng, Zhipeng; Chen, Wensheng; Cui, Wei; Liu, Jinjun; Zhu, Guo‐Qing; Kang, Yu-Ming

doi:10.1038/srep43038

Cited by 23 publications

(26 citation statements)

References 37 publications

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“…SSHTN is believed to be at least in part, neurogenic in nature. Increased sympathetic outflow has been observed in both human and animal models of SSHTN (Fujita et al, 1980 ; Gao et al, 2017 ). SSHTN is also characterized by increased AVP levels in the circulation of Dahl S rats with high salt diet (Serino et al, 2001 ).…”

Section: Discussionmentioning

confidence: 99%

Expression of Proinflammatory Cytokines Is Upregulated in the Hypothalamic Paraventricular Nucleus of Dahl Salt-Sensitive Hypertensive Rats

et al. 2018

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Accumulating evidence indicates that inflammation is implicated in hypertension. However, the role of brain proinflammatory cytokines (PICs) in salt sensitive hypertension remains to be determined. Thus, the objective of this study was to test the hypothesis that high salt (HS) diet increases PICs expression in the paraventricular nucleus (PVN) and leads to PVN neuronal activation. Eight-week-old male Dahl salt sensitive (Dahl S) rats, and age and sex matched normal Sprague Dawley (SD) rats were divided into two groups and fed with either a HS (4% NaCl) or normal salt (NS, 0.4% NaCl) diet for 5 consecutive weeks. HS diet induced hypertension and significantly increased cerebrospinal fluid (CSF) sodium concentration ([Na+]) in Dahl S rats, but not in normal SD rats. In addition, HS diet intake triggered increases in mRNA levels and immunoreactivities of PVN PICs including TNF-α, IL-6, and IL-1β, as well as Fra1, a chronic marker of neuronal activation, in Dahl S rats, but not in SD rats. Next, we investigated whether this increase in the expression of PVN PICs and Fra1 was induced by increased CSF [Na+]. Adult male SD rats were intracerebroventricular (ICV) infused with 8 μl of either hypertonic salt (4 μmol NaCl), mannitol (8 μmol, as osmolarity control), or isotonic salt (0.9% NaCl as vehicle control). Three hours following the ICV infusion, rats were euthanized and their PVN PICs expression was measured. The results showed that central administration of hypertonic saline in SD rats significantly increased the expression of PICs including TNF-α, IL-6, and IL-1β, as well as neuronal activation marker Fra1, compared to isotonic NaCl controls and osmolarity controls. Finally, we tested whether the increase in PICs expression occurred in neurons. Incubation of hypothalamic neurons with 10 mM NaCl in a culture medium for 6 h elicited significant increases in TNF-α, IL-6, and Fra1 mRNA levels. These observations, coupled with the important role of PICs in modulating neuronal activity and stimulating vasopressin release, suggest that HS intake induces an inflammatory state in the PVN, which, may in turn, augments sympathetic nerve activity and vasopressin secretion, contributing to the development of salt sensitive hypertension.

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Section: Discussionmentioning

confidence: 99%

Expression of Proinflammatory Cytokines Is Upregulated in the Hypothalamic Paraventricular Nucleus of Dahl Salt-Sensitive Hypertensive Rats

et al. 2018

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“…The aim of this study is to investigate whether IL-6 in the hypothalamic PVN exerts a protective effect against the incidence of VA after MI and whether the Gp130-STAT3 pathway plays a key role in this process. [20,21] The rats underwent sterile surgery under anaesthesia (Ulatan concentration 20%, 150 mg/kg, intraperitoneal [i.p.]) for induction of MI by ligation of the left anterior descending coronary artery (MI group) or the same surgery without ligation of the vessel (sham group).…”

Section: Intracerebroventricular Injection Of Rhil-6 Dramatically Redmentioning

confidence: 99%

Activating the interleukin-6-Gp130-STAT3 pathway ameliorates ventricular electrical stability in myocardial infarction rats by modulating neurotransmitters in the paraventricular nucleus

Gao

Yin

Chen

et al. 2020

Preprint

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Background: Malignant ventricular arrhythmia (VA) is the most common cause of death associated with acute myocardial infarction (MI). Recent studies have revealed direct involvement of the paraventricular nucleus (PVN) in the occurrence of VA. However, the underlying mechanisms remain incompletely understood. In this study, we investigated changes in the interleukin-6 (IL-6)-glycoprotein 130-signal transducer and activator of transcription 3 (STAT3) pathway in the PVN during acute MI and the effects of this pathway on ventricular stability. Methods: Rats were divided into a control group, a MI group, a PVN-injected anti-IL-6 antibody group and a PVN-injected SC144 group to observe how IL-6 and its downstream glycoprotein 130-STAT3 pathway in the PVN affect ventricular stability. The left anterior descending coronary artery was ligated to induce MI. After that, an anti-IL-6 antibody and SC144 were injected into the PVNs of rats. All data are expressed as the mean ± SE and were analysed by ANOVA with a post hoc LSD test. p<0.05 was considered to indicate statistical significance. Results: After MI, the concentration of the inflammatory factor IL-6 increased, and its downstream glycoprotein 130-STAT3 pathway was activated in the PVN. After injection of MI rat PVNs with the anti-IL-6 antibody or glycoprotein 130 inhibitor (SC144), glutamate levels increased and γ-aminobutyric acid (GABA) levels decreased in the PVN. Plasma norepinephrine concentrations also increased after treatment, which increased the vulnerability to VA. Conclusions: In summary, IL-6 in the PVN exerts a protective effect in MI rats, and the glycoprotein 130-STAT3 pathway plays a key role in this process. We anticipate that our findings will provide new ideas for the prevention and treatment of arrhythmia after MI.

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“…Immunofluorescence techniques were used to determine the expression of glial fibrillary acidic protein (GFAP), neuronal nuclei, IKKβ, and gp91 phox as described previously [43]. Antibody origin and proportion: GFAP: 1: 100, Abcam, ab33922; neuronal nuclei: 1: 100, Monoclonal Antibody, MAB377; IKKβ: 1: 300, Abcam, ab124957; gp91 phox : 1: 100, Abcam, ab129068.…”

Section: Immunofluorescencementioning

confidence: 99%

Inhibition of Hypothalamic Inhibitor κB Kinase β/Nuclear Transcription Factor κB Pathway Attenuates Metabolism and Cardiac Dysfunction in Type 2 Diabetic Rats

Chen

Liu

et al. 2019

Neuroendocrinology

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Background: Inflammation and oxidative stress play important roles in energy imbalance and its complications. Recent research indicates that hypothalamic inflammation may contribute to the pathogenesis of metabolic syndrome and cardiac dysfunction, but the mechanisms remain unclear. We hypothesized that suppression of the proinflammatory IKKβ/NF-κB pathway in the hypothalamus can improve energy balance and cardiac function in type 2 diabetic (T2D) rats. Methods: Normal and T2D rats received bilateral hypothalamic arcuate nucleus (ARC) infusions of the IKKβ inhibitor SC-514 or vehicle via osmotic minipump. Metabolic phenotyping, immunohistochemical analyses, and biochemical analyses were used to investigate the outcomes of inhibition of the hypothalamic IKKβ. Echocardiography and glucometer were used for measuring cardiac function and blood glucose, respectively. Blood samples were collected for the evaluation of circulating proinflammatory cytokines. Heart was harvested for cardiac morphology evaluations. The ARC was harvested and analyzed for IKKβ, NF-κB, proinflammatory cytokines, reactive oxygen species (ROS), and NAD(P)H (gp91 phox , p47 phox) oxidase activity levels and neuropeptides. Results: Compared with normal rats, T2D rats were characterized by hyperglycemia, hyperinsulinemia, glucose intolerance, cardiac dysfunction, as well as higher ARC levels of IKKβ, NF-κB, proinflammatory cytokines, ROS, gp91 phox , and p47 phox. ARC infusion of the IKKβ inhibitor SC-514 attenuated all these changes in T2D rats, but not in normal rats. Y.-M. Chen and X.-J. Yu contributed equally to this work.

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PVN Blockade of p44/42 MAPK Pathway Attenuates Salt-induced Hypertension through Modulating Neurotransmitters and Attenuating Oxidative Stress

Cited by 23 publications

References 37 publications

Expression of Proinflammatory Cytokines Is Upregulated in the Hypothalamic Paraventricular Nucleus of Dahl Salt-Sensitive Hypertensive Rats

Expression of Proinflammatory Cytokines Is Upregulated in the Hypothalamic Paraventricular Nucleus of Dahl Salt-Sensitive Hypertensive Rats

Activating the interleukin-6-Gp130-STAT3 pathway ameliorates ventricular electrical stability in myocardial infarction rats by modulating neurotransmitters in the paraventricular nucleus

Inhibition of Hypothalamic Inhibitor κB Kinase β/Nuclear Transcription Factor κB Pathway Attenuates Metabolism and Cardiac Dysfunction in Type 2 Diabetic Rats

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