Expression and function of COX isoforms in renal medulla: evidence for regulation of salt sensitivity and blood pressure

2006 ◽  
Vol 290 (2) ◽  
pp. F542-F549 ◽  
Author(s):  
Wenling Ye ◽  
Hui Zhang ◽  
Elaine Hillas ◽  
Donald E. Kohan ◽  
R. Lance Miller ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Salt Intake ◽  
Renal Medulla ◽  
Interstitial Cells ◽  
High Salt ◽  
Salt Loading ◽  
Arterial Blood ◽  
High Salt Intake ◽  
Cox 2 ◽  
Cox 1

Expression of cyclooxygenase (COX)-2, but not COX-1, in the renal medulla is stimulated by chronic salt loading; yet the functional implication of this phenomenon is incompletely understood. The present study examined the cellular localization and antihypertensive function of high-salt-induced COX-2 expression in the renal medulla, with a parallel assessment of the function of COX-1. COX-2 protein expression in response to high-salt loading, assessed by immunostaining, was found predominantly in inner medullary interstitial cells, whereas COX-1 protein was abundant in collecting duct (CD) and inner medullary interstitial cells and was not affected by high salt. We compared mRNA expressions of COX-1 and COX-2 in CD vs. non-CD cells isolated from aquaporin 2-green fluorescent protein transgenic mice. A low level of COX-2 mRNA, but a high level of COX-1 mRNA, as determined by real-time RT-PCR, was detected in CD compared with non-CD segments. During high-salt intake, chronic infusions of the COX-2 blocker NS-398 and the COX-1 blocker SC-560 into the renal medulla of Sprague-Dawley rats for 5 days induced ∼30- and 15-mmHg increases in mean arterial pressure, respectively. During similar high-salt intake, COX-1 knockout mice exhibited a gradual, but significant, increase in systolic blood pressure that was associated with a marked suppression of urinary PGE2 excretion. Therefore, we conclude that the two COX isoforms in the renal medulla play a similar role in the stabilization of arterial blood pressure during salt loading.

Deletion of cyclooxygenase-2 in the mouse increases arterial blood pressure with no impairment in renal NO production in response to chronic high salt intake

2013 ◽  
Vol 304 (10) ◽  
pp. R899-R907 ◽  
Author(s):  
Mette Stæhr ◽  
Pernille B. L. Hansen ◽  
Kirsten Madsen ◽  
Paul M. Vanhoutte ◽  
Rolf M. Nüsing ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Arterial Blood Pressure ◽  
Water Intake ◽  
Salt Intake ◽  
High Salt ◽  
No Production ◽  
Arterial Blood ◽  
High Salt Intake ◽  
Cox 2

Experiments were designed to test the hypothesis that cyclooxygenase-2 (COX-2) activity attenuates the blood pressure increase during high NaCl intake by stimulation of endothelial nitric oxide synthase (eNOS)-mediated NO synthesis in the kidney medulla. COX-2−/− (C57BL6) an COX-2+/+ mice were fed a diet with 0.004% (low salt, LS) or 4% (high salt, HS) NaCl for 18 days. Arterial blood pressure was recorded continuously using indwelling catheters. Food and water intake and diuresis were measured in metabolic cages. Urine osmolality and excretion of electrolytes, cGMP, cAMP, and NOx were determined, as well as plasma NOx and cGMP. There was a significant dependence of blood pressure on salt intake and genotype: COX-2−/− exhibited higher blood pressure than COX-2+/+ both on HS and LS intake. COX-2+/+ littermates displayed an increase in blood pressure on HS versus LS (102.3 ± 1.1 mmHg vs. 91.9 ± 0.9 mmHg) day and night. The mice exhibited significant blood pressure increases during the awake phase (night) that were larger in COX-2−/− on HS diet compared with COX-2+/+. Water intake, diuresis, Na+, and osmolyte excretions and NOx and cGMP excretions were significantly and similarly elevated with HS in COX-2−/− and COX-2+/+. In summary, C57BL6 mice exhibit a salt intake-dependent increase in arterial blood pressure with increased renal NO production. COX-2 activity has a general lowering effect on arterial blood pressure. COX-2 dampens NaCl-induced increases in arterial blood pressure in the awake phase. In conclusion, COX-2 activity attenuates the changes in nocturnal blood pressure during high salt intake, and COX-2 activity is not necessary for increased renal nitric oxide formation during elevated NaCl intake.

Abstract MP13: Etamicastat Prevents Arterial Blood Pressure Increase in Mice Lacking Salt-inducible Kinase 1 (SIK1)

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Nuno Pires ◽  
Bruno Igreja ◽  
Eduardo Moura ◽  
Maria João Bonifácio ◽  
Paula Serrão ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Salt Intake ◽  
Renin Angiotensin System ◽  
Fold Increase ◽  
High Salt ◽  
High Salt Diet ◽  
Urinary Catecholamines ◽  
Salt Diet ◽  
Arterial Blood ◽  
High Salt Intake

Loss of salt-inducible kinase 1 (SIK1) triggers an increase in blood pressure (BP) upon a chronic high-salt intake in mice (Circ Res 2015;116:642-52). Here, we address possible acute mechanisms that may relate to the observed high BP in mice lacking SIK1. SIK1 knockout ( sik1 -/- ) and wild-type ( sik1 +/+ ) littermate mice were challenged for seven days with a normal- (0.3% NaCl) or high-salt (8% NaCl) diet. Systolic BP (SBP) was significantly increased in sik1 -/- mice (137.0±17.2 mmHg) after seven days of high-salt intake, as compared to sik1 +/+ mice counterparts (120.6±4.5 mmHg). The renin-angiotensin system (RAS) and the sympathetic nervous system (SNS) were assayed in order to investigate the possible causes for the increase in SBP in sik1 -/- mice fed a high-salt diet. No differences in renin (normal-salt: 463.4±17.9, high-salt: 462.9±28.9 pg/ml) and angiotensin II (normal-salt: 45.8±10.0, high-salt: 39.0±8.5 pg/ml) serum levels were observed. The activity of dopamine β-hydroxylase (DβH), the enzyme that converts dopamine (DA) to norepinephrine (NE), was significantly increased in the adrenal glands of sik1 -/- mice fed a high-salt diet (356.7±32.8 nmol/mg protein) as compared to sik1 -/- mice on a normal-salt diet (184.4±14.4 nmol/mg protein). Similarly, urinary catecholamines (DA, NE, epinephrine) and L-DOPA were significantly increased (3- to 7-fold increase) in sik1 -/- mice fed a high-salt diet as compared to sik1 -/- mice on a normal-salt intake. Altogether, this data supports the view that sik1 -/- mice fed a high-salt diet develop SNS overactivity. Next, we addressed the question if reducing SNS activity in sik1 -/- mice fed a high-salt diet would ameliorate hypertension. For that purpose, the effect of etamicastat, a peripheral reversible DβH inhibitor, was evaluated on the development of high BP upon high-salt diet. Etamicastat treatment (50 mg/kg/day), started prior to high-salt feeding, completely prevented SBP increase in sik1 -/- mice fed a high-salt diet (116.8±4.7 mmHg). It is concluded that the SNS is involved in the development of salt-induced hypertension in sik1 -/- mice and that the DβH inhibitor etamicastat is able to reduce SNS overactivity and high BP in this mouse model of hypertension.

scholarly journals Eplerenone inhibits aldosterone-induced renal expression of cyclooxygenase

2012 ◽  
Vol 13 (3) ◽  
pp. 353-359 ◽  
Author(s):  
MA Bayorh ◽  
A Rollins-Hairston ◽  
J Adiyiah ◽  
D Lyn ◽  
D Eatman
Keyword(s):  
Salt Intake ◽  
High Salt ◽  
Prostaglandin E ◽  
Renal Tubules ◽  
Protective Effects ◽  
High Salt Diet ◽  
Salt Diet ◽  
High Salt Intake ◽  
Low Salt ◽  
Cox 2

Introduction: The upregulation of cyclooxygenase (COX) expression by aldosterone (ALDO) or high salt diet intake is very interesting and complex in the light of what is known about the role of COX in renal function. Thus, in this study, we hypothesize that apocynin (APC) and/or eplerenone (EPL) inhibit ALDO/salt-induced kidney damage by preventing the production of prostaglandin E2 (PGE2). Methods: Dahl salt-sensitive rats on either a low-salt or high-salt diet were treated with ALDO (0.2 mg pellet) in the presence of EPL (100 mg/kg/day) or APC (1.5 mM). Indirect blood pressure, prostaglandins and ALDO levels and histological changes were measured. Results: Cyclooxygenase-2 (COX-2) levels were upregulated in the renal tubules and peritubular vessels after high-salt intake, and APC attenuated renal tubular COX-2 protein expression induced by ALDO. Plasma PGE2 levels were significantly reduced by ALDO in the rats fed a low-salt diet when compared to rats fed a high-salt diet. PGE2 was blocked by EPL but increased in the presence of APC. Conclusions: The beneficial effects of EPL may be associated with an inhibition of PGE2. The mechanism underlying the protective effects of EPL is clearly distinct from that of APC and suggests that these agents can have differential roles in cardiovascular disease.

Abstract 142: A Fructose-but Not a Glucose-enriched Diet, Induces a Salt-dependent Increase in Blood Pressure and Enhances NKCC2 Phosphorylation in Normal Rats

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Keyona N King-Medina ◽  
Emily Henson ◽  
Pablo Ortiz
Keyword(s):  
Blood Pressure ◽  
Drinking Water ◽  
Salt Intake ◽  
Caloric Intake ◽  
High Salt ◽  
Human Consumption ◽  
Thick Ascending Limb ◽  
Sprague Dawley ◽  
High Fructose ◽  
High Salt Intake

Human consumption of fructose as a sweetener has increased in the past 30 years. High fructose intake has been implicated in the development of hypertension, diabetes, and obesity. In the US, the upper 10th percentile of the population consumes up to 40% of their caloric intake from added sugars, in which fructose represents half of these. Fructose metabolism is strikingly different from that of glucose. Yet, the effect of a fructose or glucose-enriched diet in salt handling by the kidney, affecting blood pressure, and its interaction with high salt intake has been poorly studied. In genetic models of salt-sensitive hypertension, the activity of the Na + /K + /2Cl - cotransporter (NKCC2) in the thick ascending limb (TAL) is abnormally enhanced. We hypothesized that chronic fructose in drinking water induces a salt-dependent increase in blood pressure and stimulates NKCC2 during high salt intake in normal rats. Sprague-Dawley rats were given 20% fructose or 20% glucose in drinking water for 1 week after which a high salt (HS) diet (4% Na + in chow) was started for 3 weeks. When we measured systolic blood pressure (SBP) by tail cuff plethysmography in fructose-fed and glucose-fed rats on a HS diet, only the fructose-fed rats had an increased SBP from 120±10 to 132±6 mmHg on day 7 of HS (p<0.01). SBP continued to increase up to 144±18 mmHg after 3 weeks (p<0.01 vs glucose). Fructose or glucose alone did not increase SBP after 4 weeks. We then repeated the protocol using radiotelemetry to monitor the blood pressure (BP). In rats fed fructose, by day 5 of HS the SBP increased by 12±3 mmHg (p<0.02) and SBP remained elevated for 3 weeks (delta: 10±2.5 mmHg, n=3). In rats fed glucose, a HS diet did not significantly change SBP for 3 weeks (n=5). Moreover, NKCC2 activity in the TAL is enhanced by phosphorylation at Thr96, 101. We found that NKCC2 phosphorylation was higher in rats fed fructose plus HS (p<0.02) but not in rats fed glucose plus HS for 3 weeks (HS: 100, fructose+HS: 250±40%, glucose+HS: 95±10%). Therefore, we conclude that a high fructose (but not a glucose) diet in normal rats induces a salt-dependent increase in BP independently from caloric intake. Thus, the increase in BP may in part be due to the stimulation of NKCC2 phosphorylation in the TAL by fructose.

scholarly journals The Relationship Between Urine Uromodulin and Blood Pressure Changes: The DASH-Sodium Trial

2020 ◽  
Author(s):  
Christine Y Bakhoum ◽  
Cheryl A M Anderson ◽  
Stephen P Juraschek ◽  
Casey M Rebholz ◽  
Lawrence J Appel ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Salt Intake ◽  
Control Diet ◽  
Random Order ◽  
High Salt ◽  
Thick Ascending Limb ◽  
Feeding Period ◽  
High Sodium ◽  
Sodium Diet ◽  
High Salt Intake

Abstract BACKGROUND Uromodulin modulates the sodium-potassium-two-chloride transporter in the thick ascending limb of the loop of Henle, and its overexpression in murine models leads to salt-induced hypertension. We hypothesized that individuals with higher baseline levels of urine uromodulin would have a greater increase in systolic blood pressure (SBP) for the same increase in sodium compared with those with lower uromodulin levels. METHODS We used data from 157 subjects randomized to the control diet of the Dietary Approaches to Stop Hypertension (DASH)-Sodium trial who were assigned to 30 days of low (1,500 mg/d), medium (2,400 mg/d), and high salt (3,300 mg/d) diets in random order. Blood pressure was measured prerandomization and then weekly during each feeding period. We evaluated the association of prerandomization urine uromodulin with change in SBP between diets, as measured at the end of each feeding period, using multivariable linear regression. RESULTS Baseline urine uromodulin stratified by tertiles was ≤17.64, 17.65–31.97, and ≥31.98 µg/ml. Across the tertiles, there were no significant differences in SBP at baseline, nor was there a differential effect of sodium diet on SBP across tertiles (low to high, P = 0.81). After adjusting for age, sex, body mass index, and race, uromodulin levels were not significantly associated with SBP change from low to high sodium diet (P = 0.42). CONCLUSIONS In a randomized trial of different levels of salt intake, higher urine uromodulin levels were not associated with a greater increase in blood pressure in response to high salt intake.

Prolonged NOS inhibition in the brain elevates blood pressure in normotensive rats

1998 ◽  
Vol 275 (2) ◽  
pp. R410-R417 ◽  
Author(s):  
Atsushi Sakima ◽  
Hiroshi Teruya ◽  
Masanobu Yamazato ◽  
Rijiko Matayoshi ◽  
Hiromi Muratani ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Salt Intake ◽  
High Salt ◽  
Salt Loading ◽  
Salt Diet ◽  
Intracerebroventricular Infusion ◽  
Air Jet ◽  
Sd Rats ◽  
Low Salt ◽  
The Brain

Systemic inhibition of nitric oxide synthase (NOS) evokes hypertension, which is enhanced by salt loading, partly via augmented sympathetic activity. We investigated whether inhibition of brain NOS elevates blood pressure (BP) in normotensive rats and, if so, whether the BP elevation is enhanced by salt loading. After a 2-wk low-salt (0.3%) diet, male Sprague-Dawley (SD) rats were divided into four groups. Groups 1 and 2 received a chronic intracerebroventricular infusion of 0.5 mg ⋅ kg−1 ⋅ day−1of N G-monomethyl-l-arginine (l-NMMA), and groups 3 and 4 were given artificial cerebrospinal fluid (aCSF). Groups 1 and 3 were placed on a high-salt (8%) diet, whereas groups 2 and 4 were on a low-salt diet. On day 9or 10, group 1 showed significantly higher mean arterial pressure (MAP) in a conscious unrestrained state (129 ± 3 mmHg vs. 114 ± 3, 113 ± 1, and 108 ± 3 mmHg in groups 2, 3, and 4, respectively, P < 0.05). On a high-salt diet, response of renal sympathetic nerve activity but not of BP to air-jet stress was significantly larger in rats givenl-NMMA than in rats given aCSF (29 ± 4% vs. 19 ± 3%, P < 0.05). When the intracerebroventricular infusions were continued for 3 wk, MAP was significantly higher in rats givenl-NMMA than in rats given aCSF irrespective of salt intake, although the difference was ∼7 mmHg. Thus chronic inhibition of NOS in the brain only slightly elevates BP in SD rats. Salt loading causes a more rapid rise in BP. The mechanisms of the BP elevation and its acceleration by salt loading remain to be elucidated.

scholarly journals Relationship Between Salt Intake and Blood Pressure in Hypertensive Patients in Beijing

2020 ◽  
Vol 33 (4) ◽  
pp. 371-371
Author(s):  
Hong-yi Wang ◽  
Yong-jie He ◽  
Wei Li ◽  
Fan Yang ◽  
Ning-ling Sun
Keyword(s):  
Blood Pressure ◽  
Ambulatory Blood Pressure ◽  
Salt Intake ◽  
Blood Pressure Monitoring ◽  
Urinary Sodium Excretion ◽  
High Salt ◽  
Pressure Monitoring ◽  
Hypertensive Patients ◽  
High Salt Intake ◽  
Tertiary Hospitals

Abstract Background To survey the relationship between salt intake and blood pressure in hypertensive patients in Beijing. Methods A cross-sectional survey was used. Essential hypertensive patients were enrolled and divided into three groups (low, medium, and high salt intake) according to their 24 h urinary sodium excretion, which was used to access the salt intake. Blood pressure was measured through office measurement and ambulatory blood pressure monitoring. Results A total of 2,241 patients were enrolled with a mean age of 59.5 ± 13.8 years, mean blood pressure of 141.1 ± 18.5/84.6 ± 12.7 mm Hg, and urinary sodium excretion of 163.9 (95% CI 160.3–167.4) mmol [equal to salt intake 9.59 (9.38–9.79) g/d]. There were 1,544 cases from tertiary hospitals and the other 697 cases from community hospitals. Patients from community hospitals took more salt than patients from tertiary hospitals. Patients with high salt intake were younger than patients with low and medium salt intake. There were more males in high salt intake group than in the other two groups. Ambulatory blood pressure monitoring showed that patients with high salt intake had higher mean blood pressure not only in daytime, but also at night. The diastolic blood pressure in patients with medium salt intake was higher than that in patients with low salt intake. Conclusions Higher salt intake was associated with higher ambulatory blood pressure in hypertensive patients. More effort should be made to lower salt intake to improve blood pressure control rate.

scholarly journals High Salt Intake Augments Blood Pressure Responses During Submaximal Aerobic Exercise

2020 ◽  
Vol 9 (10) ◽  
Author(s):  
Matthew C. Babcock ◽  
Austin T. Robinson ◽  
Kamila U. Migdal ◽  
Joseph C. Watso ◽  
Christopher R. Martens ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Aerobic Exercise ◽  
Salt Intake ◽  
High Salt ◽  
High Salt Intake ◽  
Submaximal Aerobic Exercise ◽  
Blood Pressure Responses
Sign in / Sign up

Export Citation Format

Share Document