Renal NF-κB activation and TNF-α upregulation correlate with salt-sensitive hypertension in Dahl salt-sensitive rats

2006 ◽  
Vol 291 (6) ◽  
pp. R1817-R1824 ◽  
Author(s):  
Jian-Wei Gu ◽  
Niu Tian ◽  
Megan Shparago ◽  
Wei Tan ◽  
Amelia P. Bailey ◽  
...  
Keyword(s):  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
Molecular Mechanisms ◽  
Sodium Concentration ◽  
Interferon Γ ◽  
Binding Activity ◽  
Proinflammatory Response ◽  
Mobility Shift ◽  
Low Sodium Diet ◽  
Tnf Α

Molecular mechanisms of salt-sensitive (SS) hypertension related to renal inflammation have not been defined. We seek to determine whether a high-salt (HS) diet induces renal activation of NF-κB and upregulation of TNF-α related to the development of hypertension in Dahl SS rats. Six 8-wk-old male Dahl SS rats received a HS diet (4%), and six Dahl SS rats received a low-sodium diet (LS, 0.3%) for 5 wk. In the end, mean arterial pressure was determined in conscious rats by continuous monitoring through a catheter placed in the carotid artery. Mean arterial pressure was significantly higher in the HS than the LS group (177.9 ± 3.7 vs. 109.4 ± 2.9 mmHg, P < 0.001). There was a significant increase in urinary albumin secretion in the HS group compared with the LS group (22.3 ± 2.6 vs. 6.1 ± 0.7 mg/day; P < 0.001). Electrophoretic mobility shift assay demonstrated that the binding activity of NF-κB p65 proteins in the kidneys of Dahl SS rats was significantly increased by 53% in the HS group compared with the LS group ( P = 0.007). ELISA indicated that renal protein levels of TNF-α, but not IL-6, interferon-γ, and CCL28, were significantly higher in the HS than the LS group (2.3 ± 0.8 vs. 0.7 ± 0.2 pg/mg; P = 0.036). We demonstrated that plasma levels of TNF-α were significantly increased by fivefold in Dahl SS rats on a HS diet compared with a LS diet. Also, we found that increased physiologically relevant sodium concentration (10 mmol/l) directly stimulated NF-κB activation in cultured human renal proximal tubular epithelial cells. These findings support the hypothesis that activation of NF-κB and upregulation of TNF-α are the important renal mechanisms linking proinflammatory response to SS hypertension.

scholarly journals Angiotensin II utilizes Janus kinase 2 in hypertension, but not in the physiological control of blood pressure, during low-salt intake

2011 ◽  
Vol 301 (4) ◽  
pp. R1169-R1176 ◽  
Author(s):  
Amy K. L. Banes-Berceli ◽  
Hind Al-Azawi ◽  
Daniel Proctor ◽  
Harvey Qu ◽  
Dominic Femminineo ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
Janus Kinase ◽  
Ang Ii ◽  
Physiological Control ◽  
Sodium Diet ◽  
Low Sodium Diet ◽  
Low Sodium ◽  
Low Salt

Janus kinase (JAK) 2 is activated by ANG II in vitro and in vivo, and chronic blockade of JAK2 by the JAK2 inhibitor AG-490 has been shown recently to attenuate ANG II hypertension in mice. In this study, AG-490 was infused intravenously in chronically instrumented rats to determine if the blunted hypertension was linked to attenuation of the renal actions of ANG II. In male Sprague-Dawley rats, after a control period, ANG II at 10 ng·kg−1·min−1 was infused intravenously with or without AG-490 at 10 ng·kg−1·min−1 iv for 11 days. ANG II infusion (18 h/day) increased mean arterial pressure from 91 ± 3 to 168 ± 7 mmHg by day 11. That response was attenuated significantly in the ANG II + AG-490 group, with mean arterial pressure increasing only from 92 ± 5 to 127 ± 3 mmHg. ANG II infusion markedly decreased urinary sodium excretion, caused a rapid and sustained decrease in glomerular filtration rate to ∼60% of control, and increased renal JAK2 phosphorylation; all these responses were blocked by AG-490. However, chronic AG-490 treatment had no effect on the ability of a separate group of normal rats to maintain normal blood pressure when they were switched rapidly to a low-sodium diet, whereas blood pressure fell dramatically in losartan-treated rats on a low-sodium diet. These data suggest that activation of the JAK/STAT pathway is critical for the development of ANG II-induced hypertension by mediating its effects on renal sodium excretory capability, but the physiological control of blood pressure by ANG II with a low-salt diet does not require JAK2 activation.

IL-17 stimulates inflammatory responses via NF-κB and MAP kinase pathways in human colonic myofibroblasts

2002 ◽  
Vol 282 (6) ◽  
pp. G1035-G1044 ◽  
Author(s):  
Kazunori Hata ◽  
Akira Andoh ◽  
Mitsue Shimada ◽  
Sanae Fujino ◽  
Shigeki Bamba ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Northern Blotting ◽  
Binding Activity ◽  
Mitogen Activated Protein Kinase ◽  
Mobility Shift ◽  
Dna Binding Activity ◽  
Tnf Α ◽  
Mobility Shift Assay ◽  
Mapk Inhibitors ◽  
Gel Mobility Shift

Colonic subepithelial myofibroblasts (SEMFs) may play a role in the modulation of mucosal inflammatory responses. We investigated the effects of interleukin (IL)-17 on IL-6 and chemokine [IL-8 and monocyte chemoattractant protein (MCP)-1] secretion in colonic SEMFs. Cytokine expression was determined by ELISA and Northern blotting. Nuclear factor kappa B (NF-κB) DNA-binding activity was evaluated by electrophortetic gel mobility shift assay (EMSA). The activation of mitogen-activated protein kinase (MAPK) was assessed by immunoblotting. IL-6, IL-8, and MCP-1 secretions were rapidly induced by IL-17. IL-17 induced NF-κB activation within 45 min after stimulation. A blockade of NF-κB activation markedly reduced these responses. MAPK inhibitors (SB-203580, PD-98059, and U-0126) significantly reduced the IL-17-induced IL-6 and chemokine secretion. The combination of either IL-17 + IL-1β or IL-17 + tumor necrosis factor (TNF)-α enhanced cytokine secretion; in particular, the effects of IL-17 + TNF-α on IL-6 secretion were much stronger than the other responses. This was dependent on the enhancement of IL-6 mRNA stability. In conclusion, human SEMFs secreted IL-6, IL-8, and MCP-1 in response to IL-17. These responses might play an important role in the pathogenesis of gut inflammation.

scholarly journals Neuron-Derived Extracellular Vesicles Modulate Microglia Activation and Function

Biology ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 948
Author(s):  
Hui Peng ◽  
Brock T. Harvey ◽  
Christopher I. Richards ◽  
Kimberly Nixon
Keyword(s):  
Extracellular Vesicles ◽  
Cortical Neurons ◽  
Molecular Mechanisms ◽  
Proinflammatory Response ◽  
Tnf Α ◽  
Rat Cortical Neurons ◽  
The Central Nervous System ◽  
And Function ◽  
And Control ◽  
Brain Homeostasis

Microglia act as the immune cells of the central nervous system (CNS). They play an important role in maintaining brain homeostasis but also in mediating neuroimmune responses to insult. The interactions between neurons and microglia represent a key process for neuroimmune regulation and subsequent effects on CNS integrity. However, the molecular mechanisms of neuron-glia communication in regulating microglia function are not fully understood. One recently described means of this intercellular communication is via nano-sized extracellular vesicles (EVs) that transfer a large diversity of molecules between neurons and microglia, such as proteins, lipids, and nucleic acids. To determine the effects of neuron-derived EVs (NDEVs) on microglia, NDEVs were isolated from the culture supernatant of rat cortical neurons. When NDEVs were added to primary cultured rat microglia, we found significantly improved microglia viability via inhibition of apoptosis. Additionally, application of NDEVs to cultured microglia also inhibited the expression of activation surface markers on microglia. Furthermore, NDEVs reduced the LPS-induced proinflammatory response in microglia according to reduced gene expression of proinflammatory cytokines (TNF-α, IL-6, MCP-1) and iNOS, but increased expression of the anti-inflammatory cytokine, IL-10. These findings support that neurons critically regulate microglia activity and control inflammation via EV-mediated neuron–glia communication. (Supported by R21AA025563 and R01AA025591).

Vasopressin response to hyperosmolality and hypotension during ovine pregnancy

1994 ◽  
Vol 266 (1) ◽  
pp. R188-R193 ◽  
Author(s):  
M. Keller-Wood
Keyword(s):  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
Arginine Vasopressin ◽  
Sodium Concentration ◽  
Plasma Sodium ◽  
Arterial Blood ◽  
Plasma Sodium Concentration ◽  
Blood Pressures ◽  
The Mean ◽  
Pregnant State

The arginine vasopressin (AVP) responses to hyperosmolality and to hypotension were compared in pregnant and nonpregnant ewes. When the responses to infusion of normal or hypertonic saline were compared, plasma AVP and Na+ concentrations were lower in pregnant ewes than nonpregnant ewes, but the relation between plasma AVP and Na+ concentrations was not altered in the pregnant state. In a second study the AVP response to hypotension, induced by the infusion of 2.5, 5.0, or 10.0 micrograms nitroprusside.kg-1.min-1, was compared in pregnant and nonpregnant ewes. Despite significantly lower mean arterial blood pressures in the pregnant ewes, the mean plasma AVP concentration after infusion of nitroprusside was not increased during pregnancy. Therefore, the relation between mean arterial pressure and AVP was significantly shifted to the left in the pregnant ewes, indicating lower AVP concentrations for a given level of arterial pressure during pregnancy. The results suggest that pregnancy alters the regulation of AVP by arterial pressure but does not affect the regulation of AVP by plasma sodium concentration in the ewe.

Regulation of surfactant proteins A and B by TNF-α and phorbol ester independent of NF-κB

1998 ◽  
Vol 274 (2) ◽  
pp. L289-L295 ◽  
Author(s):  
Gloria S. Pryhuber ◽  
Rubia Khalak ◽  
Qian Zhao
Keyword(s):  
Phorbol Ester ◽  
Regulation Of Gene Expression ◽  
Protein Composition ◽  
Binding Activity ◽  
Surfactant Proteins ◽  
Pyrrolidine Dithiocarbamate ◽  
Acute Lung Inflammation ◽  
Mobility Shift ◽  
Mrna Accumulation ◽  
Tnf Α

Acute lung inflammation is complicated by altered pulmonary surfactant phospholipid and protein composition. The proinflammatory cytokine tumor necrosis factor-α (TNF-α) and the phorbol ester 12- O-tetradecanoyl phorbol-13-acetate (TPA) inhibit expression of surfactant-associated proteins A and B (SP-A and SP-B), both important for normal surfactant function. The transcription factor nuclear factor-κB (NF-κB) frequently mediates regulation of gene expression by TPA and TNF-α. In the present study, electrophoretic mobility shift assays (EMSAs) and pyrrolidine dithiocarbamate (PDTC), an inhibitor of NF-κB activation, were utilized to determine the role of NF-κB activation in TPA and TNF-α inhibition of the surfactant proteins in NCI-H441 cells. Pentoxifylline (PTX), which inhibits TNF-α cellular effects without preventing NF-κB activation, was also tested. By EMSA, TPA and TNF-α increased nuclear NF-κB binding activity in temporally distinct patterns. PDTC decreased TPA- and TNF-α-induced NF-κB binding activity but did not limit their inhibition of SP-A and SP-B mRNAs. PDTC independently decreased both SP-A and SP-B mRNAs. PTX partially reversed TNF-α- but not TPA-mediated inhibition of SP-A and SP-B mRNAs without altering NF-κB binding. The effects of PDTC and PTX on NF-κB and the surfactant proteins suggest that NF-κB activation does not mediate TPA or TNF-α inhibition of SP-A and SP-B mRNA accumulation.

scholarly journals Transcription factor ΔFosB acts within the nucleus of the solitary tract to increase mean arterial pressure during exposures to intermittent hypoxia

2018 ◽  
Vol 314 (2) ◽  
pp. H270-H277 ◽  
Author(s):  
Qiong Wu ◽  
J. Thomas Cunningham ◽  
Steve Mifflin
Keyword(s):  
Sleep Apnea ◽  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
Intermittent Hypoxia ◽  
Molecular Mechanisms ◽  
Viral Vector ◽  
Constitutive Expression ◽  
Dominant Negative ◽  
Ventrolateral Medulla ◽  
Solitary Tract

ΔFosB is a member of the activator protein-1 family of transcription factors. ΔFosB has low constitutive expression in the central nervous system and is induced after exposure of rodents to intermittent hypoxia (IH), a model of the arterial hypoxemia that accompanies sleep apnea. We hypothesized ΔFosB in the nucleus of the solitary tract (NTS) contributes to increased mean arterial pressure (MAP) during IH. The NTS of 11 male Sprague-Dawley rats was injected (3 sites, 100 nl/site) with a dominant negative construct against ΔFosB (ΔJunD) in an adeno-associated viral vector (AAV)-green fluorescent protein (GFP) reporter. The NTS of 10 rats was injected with AAV-GFP as sham controls. Two weeks after NTS injections, rats were exposed to IH for 8 h/day for 7 days, and MAP was recorded using telemetry. In the sham group, 7 days of IH increased MAP from 99.8 ± 1.1 to 107.3 ± 0.5 mmHg in the day and from 104.4 ± 1.1 to 109.8 ± 0.6 mmHg in the night. In the group that received ΔJunD, IH increased MAP during the day from 95.9 ± 1.7 to 101.3 ± 0.4 mmHg and from 100.9 ± 1.7 to 102.8 ± 0.5 mmHg during the night (both IH-induced changes in MAP were significantly lower than sham, P < 0.05). After injection of the dominant negative construct in the NTS, IH-induced ΔFosB immunoreactivity was decreased in the paraventricular nucleus ( P < 0.05); however, no change was observed in the rostral ventrolateral medulla. These data indicate that ΔFosB within the NTS contributes to the increase in MAP induced by IH exposure. NEW & NOTEWORTHY The results of this study provides new insights into the molecular mechanisms that mediate neuronal adaptations during exposures to intermittent hypoxia, a model of the hypoxemias that occur during sleep apnea. These adaptations are noteworthy as they contribute to the persistent increase in blood pressure induced by exposures to intermittent hypoxia.

scholarly journals Decreased alveolar oxygen induces lung inflammation

2003 ◽  
Vol 284 (2) ◽  
pp. L360-L367 ◽  
Author(s):  
C. Madjdpour ◽  
U. R. Jewell ◽  
S. Kneller ◽  
U. Ziegler ◽  
R. Schwendener ◽  
...  
Keyword(s):  
Lung Injury ◽  
Alveolar Macrophages ◽  
Inflammatory Mediators ◽  
Molecular Mechanisms ◽  
Hypoxia Inducible Factor ◽  
Lavage Fluid ◽  
Binding Activity ◽  
Intercellular Adhesion Molecule ◽  
Tnf Α ◽  
Alveolar Hypoxia

Molecular mechanisms of the inflammatory reaction in hypoxia-induced lung injury are not well defined. Therefore, effects of alveolar hypoxia were studied in rat lungs, exposing rats to 10% oxygen over periods of 1, 2, 4, 6, and 8 h. An increase in the number of macrophages in bronchoalveolar lavage fluid of hypoxic animals was shown between 1 and 8 h. Extravasation of albumin was enhanced after 1 h and remained increased throughout the study period. NF-κB-binding activity as well as mRNA for TNF-α, macrophage inflammatory protein (MIP)-1β, and monocyte chemoattractant protein (MCP)-1 were increased within the first 2 h of exposure to hypoxia. Hypoxia-inducible factor (HIF)-1α and intercellular adhesion molecule (ICAM)-1 mRNA were upregulated between 1 and 6 h. Elimination of alveolar macrophages by intratracheal application of liposome-encapsulated clodronate led to a decreased expression of NF-κB binding activity, HIF-1α, TNF-α, ICAM-1, and MIP-1β. In summary, alveolar hypoxia induced macrophage recruitment, an increase in albumin leakage, and enhanced expression of inflammatory mediators, which were mainly macrophage dependent. Alveolar macrophages appear to have a prominent role in the inflammatory response in hypoxia-induced lung injury and the related upregulation of inflammatory mediators.

scholarly journals Interleukin-4 supplementation improves the pathophysiology of hypertension in response to placental ischemia in RUPP rats

2019 ◽  
Vol 316 (2) ◽  
pp. R165-R171 ◽  
Author(s):  
Jesse N. Cottrell ◽  
Lorena M. Amaral ◽  
Ashlyn Harmon ◽  
Denise C. Cornelius ◽  
Mark W. Cunningham ◽  
...  
Keyword(s):  
B Cells ◽  
Mean Arterial Pressure ◽  
Natural Killer Cells ◽  
Arterial Pressure ◽  
Natural Killer ◽  
Interleukin 4 ◽  
Th2 Cells ◽  
Killer Cells ◽  
Tnf Α ◽  
Placental Ischemia

Preeclampsia (PE) is characterized by chronic inflammation and elevated agonistic autoantibodies to the angiotensin type 1 receptor (AT1-AA), endothelin-1, and uterine artery resistance index (UARI) during pregnancy. Previous studies report an imbalance among immune cells, with T-helper type 2 (Th2) cells being decreased during PE. We hypothesized that interleukin-4 (IL-4) would increase Th2 cells and improve the pathophysiology in response to placental ischemia during pregnancy. IL-4 (600 ng/day) was administered via osmotic minipump on gestational day 14 to normal pregnant (NP) and reduced uterine perfusion pressure (RUPP) rats. Carotid catheters were inserted, and Doppler ultrasound was performed on gestational day 18. Blood pressure (mean arterial pressure), TNF-α, IL-6, AT1-AA, natural killer cells, Th2 cells, and B cells were measured on gestational day 19. Mean arterial pressure was 97 ± 2 mmHg in NP ( n = 9), 101 ± 3 mmHg in IL-4-treated NP ( n = 14), and 137 ± 4 mmHg in RUPP ( n = 8) rats and improved to 108 ± 3 mmHg in IL-4-treated RUPP rats ( n = 17) ( P < 0.05). UARI was 0.5 ± 0.03 in NP and 0.8 in RUPP rats and normalized to 0.5 in IL-4-treated RUPP rats ( P < 0.05). Plasma nitrate-nitrite levels increased in IL-4-treated RUPP rats, while placental preproendothelin-1 expression, plasma TNF-α and IL-6, and AT1-AA decreased in IL-4-treated RUPP rats compared with untreated RUPP rats ( P < 0.05). Circulating B cells and placental cytolytic natural killer cells decreased after IL-4 administration, while Th2 cells increased in IL-4-treated RUPP compared with untreated RUPP rats. This study illustrates that IL-4 decreased inflammation and improved Th2 numbers in RUPP rats and, ultimately, improved hypertension in response to placental ischemia during pregnancy.

Evidence that the Acute Cardiovascular Response to Isoprenaline is Partly Mediated via Renin Release

1979 ◽  
Vol 57 (1) ◽  
pp. 13-18 ◽  
Author(s):  
G. H. Anderson
Keyword(s):  
Angiotensin Ii ◽  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
Plasma Renin Activity ◽  
Infusion Rate ◽  
Plasma Renin ◽  
Renin Activity ◽  
Sodium Diet ◽  
Low Sodium Diet ◽  
Low Sodium

1. The possible effect of the increased plasma renin activity induced by β−adrenoreceptor stimulation in supporting arterial pressure has been studied in five normal subjects on a diet of 100 mmol of sodium/day for 4 days or 40 mmol of sodium/day for 4 days by infusing isoprenaline at 1·0, 2·0 or 3·0 μg min−170 kg−1, each for 1 h with 45 min between each infusion rate. During the last 30 min of each isoprenaline dose, the angiotensin II analogue [Sar1, Ala8]angiotensin II (saralasin) was infused. 2. Isoprenaline significantly (at least P <0·05) increased the pulse rate, systolic arterial pressure and plasma renin activity; the diastolic blood pressure decreased but the mean arterial pressure did not change. Saralasin administered to subjects on the 100 mmol of sodium/day diet significantly (at least P < 0·05) lowered mean arterial pressure at the two highest isoprenaline infusion rates. 3. With patients on a low sodium diet, saralasin lowered mean arterial pressure at all three isoprenaline infusion rates. On the low sodium diet the fall in mean arterial pressure caused by saralasin was significantly greater (P < 0·05) at the isoprenaline infusion rate of 3·0 μg min−1 70 kg−1 than at the infusion rate of 1·0 μg min−1 70 kg−1. The change in mean arterial pressure with saralasin before and during isoprenaline infusion on both diets was significantly correlated (r = −0·39, n = 38, P < 0·01) with the plasma renin activity measured immediately before saralasin infusion. 4. It is concluded that during β−adrenoreceptor stimulation the increased plasma renin activity (acting through angiotensin) supports arterial pressure.

scholarly journals The impaired transcription factor AP-1 DNA binding activity in lymphocytes derived from subjects with some symptoms of premature aging.

1993 ◽  
Vol 40 (2) ◽  
pp. 269-272 ◽  
Author(s):  
E Sikora ◽  
E Radziszewska ◽  
T Kmieć ◽  
D Maślińska
Keyword(s):  
Dna Binding ◽  
Cellular Senescence ◽  
Molecular Mechanisms ◽  
Replicative Senescence ◽  
Binding Activity ◽  
Premature Aging ◽  
Mobility Shift ◽  
Dna Binding Activity ◽  
Premature Aging Syndromes

The study of human disorders known as premature aging syndromes may provide insight into the mechanisms of cellular senescence. The main feature of cellular senescence in vitro is cessation of cell proliferation. Down syndrome (DS) and neuronal ceroid-lypofuscinosis (NCL) are clinically characterized by the premature onset of numerous features normally associated with human aging. Phytohemagglutinin stimulated lymphocytes derived from DS subjects showed a statistically significant diminished proliferation capacity in comparison with lymphocytes derived from NCL and healthy individuals. We demonstrated, by applying the electrophoretic mobility shift assay, slightly impaired AP-1 DNA binding activity in NCL lymphocytes and strong in DS ones. Our results showed that the same molecular mechanisms of proliferation cessation could exist in fibroblasts characterized by replicative senescence and in lymphocytes derived from individuals with premature aging syndromes (Down).

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