scholarly journals Activation of Mineralocorticoid Receptors by Exogenous Glucocorticoids and the Development of Cardiovascular Inflammatory Responses in Adrenalectomized Rats

Endocrinology ◽  
2010 ◽  
Vol 151 (6) ◽  
pp. 2622-2628 ◽  
Author(s):  
Morag J. Young ◽  
James Morgan ◽  
Kim Brolin ◽  
Peter J. Fuller ◽  
John W. Funder
Keyword(s):  
Cardiac Fibrosis ◽  
Inflammatory Responses ◽  
Salt Intake ◽  
Hydroxysteroid Dehydrogenase ◽  
Tissue Growth ◽  
Mrna Levels ◽  
Sprague Dawley ◽  
High Salt Intake ◽  
Adrenalectomized Rats

Activation of the mineralocorticoid receptor (MR) in the context of a high salt intake produces cardiovascular inflammation plus cardiac fibrosis and failure. Inactivation of vascular 11β-hydroxysteroid dehydrogenase type 2 activity in intact animals by carbenoxolone (CBX) produces a similar pathology, presumably reflecting coronary vascular MR activation by endogenous glucocorticoids. To test this hypothesis, we have used adrenalectomized rats, without endogenous corticosteroids, and examined the consequences of corticosterone (CORT) replacement on a series of cardiovascular disease parameters. Uninephrectomized adrenalectomized Sprague Dawley rats given 1% NaCl/0.3% KCl to drink were treated for 8 d as follows: control; 20 mg deoxycorticosterone (DOC); 2 mg/d CORT; 2.5 mg/d CBX; CORT plus CBX (CORT/CBX); and CORT/CBX plus 100 mg/kg·d eplerenone. Markers of cardiac oxidative stress (p22phox and NOX4 mRNA) were up-regulated in the DOC and CORT/CBX groups; in contrast, inflammatory cell infiltration was increased and endothelial nitric oxide synthase down-regulated by CORT as well as by DOC and CORT/CBX. In the kidney, connective tissue growth factor mRNA levels were increased by DOC and CORT/CBX; in contrast, DOC had no effect on mRNA levels for channel inducing factor or endothelin 3, which were elevated only by CORT/CBX. All changes noted were reversed by eplerenone. Rats given 10-fold lower CORT (0.2 mg/d) with or without CBX showed no change in any parameter. These results suggest that there exist distinct but overlapping ligand-specific MR-mediated tissue responses to a classic mineralocorticoid (DOC) and to the glucocorticoid CORT, in the presence and absence of CBX to block vascular 11β-hydroxysteroid dehydrogenase type 2.

scholarly journals Early Inflammatory Responses in Experimental Cardiac Hypertrophy and Fibrosis: Effects of 11β-Hydroxysteroid Dehydrogenase Inactivation

Endocrinology ◽  
2003 ◽  
Vol 144 (3) ◽  
pp. 1121-1125 ◽  
Author(s):  
Morag J. Young ◽  
Leon Moussa ◽  
Rod Dilley ◽  
John W. Funder
Keyword(s):  
Inflammatory Responses ◽  
Salt Intake ◽  
Hydroxysteroid Dehydrogenase ◽  
Target Tissue ◽  
Protective Enzyme ◽  
Etiologic Role ◽  
High Salt Intake ◽  
Tissue Selectivity ◽  
Drinking Solution

In epithelial tissues such as kidney, mineralocorticoid receptors (MR) are protected against glucocorticoid occupancy by the enzyme 11β-hydroxysteroid dehydrogenase (11βHSD) type 2. If the enzyme is congenitally inactive, or blocked by carbenoxolone, physiologic glucocorticoids act as MR agonists in such tissues. In most nonepithelial tissues, including cardiomyocytes, 11βHSD2 is expressed at minimal levels; in these tissues physiologic glucocorticoids act as MR antagonists, with the basis for this tissue selectivity currently unknown. Vascular smooth muscle cells (VSMC) express MR and 11βHSD1/2, with 11βHSD1 reported to show uncharacteristic oxidase activity, so that VSMC thus constitute a potential physiologic aldosterone target tissue. Because mineralocorticoid/salt administration triggers marked inflammatory responses in coronary vasculature, we reasoned that VSMC (like epithelial) MR may be activated by glucocorticoids if the protective enzyme is blocked. We thus gave uninephrectomized rats 0.9% NaCl solution to drink, and deoxycorticosterone (DOC, as a single 20 mg sc dose) or carbenoxolone (CBX, 2.5 mg/d in the drinking solution). Both DOC and CBX increased systolic blood pressure, heart, and kidney weight, and expression of cyclooxygenase 2, ED-1-positive macrophages, and osteopontin, with effects of both DOC and CBX blocked by the selective MR antagonist eplerenone. These findings suggest that local glucocorticoid excess, reflecting lower VSMC 11βHSD1/2 activity may mimic systemic mineralocorticoid excess, and play a direct etiologic role in coronary vascular inflammatory responses under circumstances of a high salt intake.

scholarly journals Differential responses to salt supplementation in adult male and female rat adrenal glands following intrauterine growth restriction

2011 ◽  
Vol 209 (1) ◽  
pp. 85-94 ◽  
Author(s):  
Karine Bibeau ◽  
Mélissa Otis ◽  
Jean St-Louis ◽  
Nicole Gallo-Payet ◽  
Michèle Brochu
Keyword(s):  
Protein Expression ◽  
Adrenal Glands ◽  
Salt Intake ◽  
High Salt ◽  
Receptor Subtypes ◽  
Mrna Levels ◽  
Female Rat ◽  
Angiotensin Ii Receptor ◽  
Intrauterine Growth ◽  
High Salt Intake

In low sodium-induced intrauterine growth restricted (IUGR) rat, foetal adrenal steroidogenesis as well as the adult renin–angiotensin–aldosterone system (RAAS) is altered. The aim of the present study was to determine the expression of cytochrome P450 aldosterone synthase (P450aldo) and of angiotensin II receptor subtypes 1 (AT1R) and 2 (AT2R) in adult adrenal glands and whether this expression could be influenced by IUGR and by high-salt intake in a sex-specific manner. After 6 weeks of 0.9% NaCl supplementation, plasma renin activity, P450aldo expression and serum aldosterone levels were decreased in all groups. In males, IUGR induced an increase in AT1R, AT2R, and P450aldo levels, without changes in morphological appearance of the zona glomerulosa (ZG). By contrast, in females, IUGR had no effect on the expression of AT1R, but increased AT2R mRNA while decreasing protein expression of AT2R and P450aldo. In males, salt intake in IUGR rats reduced both AT1R mRNA and protein, while for AT2R, mRNA levels decreased whereas protein expression increased. In females, salt intake reduced ZG size in IUGR but had no affect on AT1R or AT2R expression in either group. These results indicate that, in response to IUGR and subsequently to salt intake, P450aldo, AT1R, and AT2R levels are differentially expressed in males and females. However, despite these adrenal changes, adult IUGR rats display adequate physiological and adrenal responses to high-salt intake, via RAAS inhibition, thus suggesting that extra-adrenal factors likely compensate for ZG alterations induced by IUGR.

Mediators of mineralocorticoid receptor-induced profibrotic inflammatory responses in the heart

2009 ◽  
Vol 116 (9) ◽  
pp. 731-739 ◽  
Author(s):  
Peter Wilson ◽  
James Morgan ◽  
John W. Funder ◽  
Peter J. Fuller ◽  
Morag J. Young
Keyword(s):  
Oxidative Stress ◽  
Mrna Expression ◽  
Mineralocorticoid Receptor ◽  
Time Course ◽  
Cardiac Fibrosis ◽  
Inflammatory Responses ◽  
Receptor Activation ◽  
Mrna Levels ◽  
Tissue Remodelling ◽  
Perivascular Inflammation

Coronary, vascular and perivascular inflammation in rats following MR (mineralocorticoid receptor) activation plus salt are well-characterized precursors for the appearance of cardiac fibrosis. Endogenous corticosterone, in the presence of the 11βHSD2 (11β hydroxysteroid dehydrogenase type 2) inhibitor CBX (carbenoxolone) plus salt, produces similar inflammatory responses and tissue remodelling via activation of MR. MR-mediated oxidative stress has previously been suggested to account for these responses. In the present study we thus postulated that when 11βHSD2 is inhibited, endogenous corticosterone bound to unprotected MR in the vessel wall may similarly increase early biomarkers of oxidative stress. Uninephrectomized rats received either DOC (deoxycorticosterone), CBX or CBX plus the MR antagonist EPL (eplerenone) together with 0.9% saline to drink for 4, 8 or 16 days. Uninephrectomized rats maintained on 0.9% saline for 8 days served as controls. After 4 days, both DOC and CBX increased both macrophage infiltration and mRNA expression of the p22phox subunit of NADPH oxidase, whereas CBX, but not DOC, increased expression of the NOX2 (gp91phox) subunit. eNOS [endothelial NOS (NO synthase)] mRNA expression significantly decreased from 4 days for both treatments, and iNOS (inducible NOS) mRNA levels increased after 16 days of DOC or CBX; co-administration of EPL inhibited all responses to CBX. The responses characterized over this time course occurred before measurable increases in cardiac hypertrophy or fibrosis. The findings of the present study support the hypothesis that endogenous corticosterone in the presence of CBX can activate vascular MR to produce both inflammatory and oxidative tissue responses well before the onset of fibrosis, that the two MR ligands induce differential but overlapping patterns of gene expression, and that elevation of NOX2 subunit levels does not appear necessary for full expression of MR-mediated inflammatory and fibrogenic responses.

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 Increased blood pressure, aldosterone activity, and regional differences in renal ENaC protein during vasopressin escape

2004 ◽  
Vol 287 (5) ◽  
pp. F1076-F1083 ◽  
Author(s):  
Jian Song ◽  
Xinqun Hu ◽  
Osman Khan ◽  
Ying Tian ◽  
Joseph G. Verbalis ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Regional Differences ◽  
Water Retention ◽  
Urine Volume ◽  
Hydroxysteroid Dehydrogenase ◽  
Plasma Aldosterone ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Sustained Increase

The syndrome of inappropriate antidiuretic hormone (SIADH) is associated with water retention and hyponatremia. The kidney adapts via a transient natriuresis and persistent diuresis, i.e., vasopressin escape. Previously, we showed an increase in the whole kidney abundance of aldosterone-sensitive proteins, the α- and γ (70-kDa-band)-subunits of the epithelial Na+ channel (ENaC), and the thiazide-sensitive Na-Cl cotransporter (NCC) in our rat model of SIADH. Here we examine mean arterial pressure via radiotelemetry, aldosterone activity, and cortical vs. medullary ENaC subunit and 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD-2) protein abundances in escape. Eighteen male Sprague-Dawley rats (300 g) were sham operated ( n = 6) or infused with desmopressin (dDAVP; n = 12, a V2 receptor-selective analog of AVP). After 4 days, one-half of the rats receiving dDAVP were switched to a liquid diet, i.e., water loaded (WL) for 5–7 additional days. The WL rats had a sustained increase in urine volume and blood pressure (122 vs. 104 mmHg, P < 0.03, at 7 days). Urine and plasma aldosterone levels were increased in the WL group to 844 and 1,658% of the dDAVP group, respectively. NCC and α- and γ-ENaC (70-kDa band) were increased significantly in the WL group (relative to dDAVP), only in the cortex. β- and γ-ENaC (85-kDa band) were increased significantly by dDAVP in cortex and medulla relative to control. 11β-HSD-2 was increased by dDAVP in the cortex and not significantly affected by water loading. These changes may serve to attenuate Na+ losses and ameliorate hyponatremia in vasopressin escape.

scholarly journals Reduced Placental 11β-Hydroxysteroid Dehydrogenase Type 2 mRNA Levels in Human Pregnancies Complicated by Intrauterine Growth Restriction: An Analysis of Possible Mechanisms

2001 ◽  
Vol 86 (10) ◽  
pp. 4979-4983 ◽  
Author(s):  
C. L. McTernan ◽  
N. Draper ◽  
H. Nicholson ◽  
S. M. Chalder ◽  
P. Driver ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Intrauterine Growth Restriction ◽  
Subsequent Development ◽  
Hydroxysteroid Dehydrogenase ◽  
Underlying Mechanism ◽  
Growth Restriction ◽  
Mrna Levels ◽  
Intrauterine Growth ◽  
Apparent Mineralocorticoid Excess

11β-Hydroxysteroid dehydrogenase type 2 (11β-HSD2) inactivates cortisol to cortisone. In the placenta 11β-HSD2 activity is thought to protect the fetus from the deleterious effects of maternal glucocorticoids. Patients with apparent mineralocorticoid excess owing to mutations in the 11β-HSD2 gene invariably have reduced birth weight, and we have recently shown reduced placental 11β-HSD2 activity in pregnancies complicated by intrauterine growth restriction. This is reflected in the literature by evidence of hypercortisolemia in the fetal circulation of small babies. In this study we have determined the levels of placental 11β-HSD2 mRNA expression across normal gestation (n = 86 placentae) and in pregnancies complicated by intrauterine growth restriction (n = 19) and evaluated the underlying mechanism for any aberrant 11β-HSD2 mRNA expression in intrauterine growth restriction. 11β-HSD2 mRNA expression increased more than 50-fold across gestation, peaking at term. Placental 11β-HSD2 mRNA levels were significantly decreased in intrauterine growth restriction pregnancies when compared with gestationally matched, appropriately grown placentae [e.g. at termΔ Ct (11β-hydroxysteroid dehydrogenase type 2/18S) 12.8 ± 0.8 (mean ± se) vs. 10.2 ± 0.2, respectively, P &lt; 0.001]. These differences were not attributable to changes in trophoblast mass in intrauterine growth restriction placentae, as assessed by parallel analyses of cytokeratin-8 mRNA expression. No mutations were found in the 11β-HSD2 gene in the intrauterine growth restriction cohort, and imprinting analysis revealed that the 11β-HSD2 gene was not imprinted. Although the underlying cause is unknown, 11β-HSD2 gene expression is reduced in intrauterine growth restriction pregnancies. These data highlight the important role of 11β-HSD2 in regulating fetal growth, a known factor in determining fetal morbidity but also the subsequent development of cardiovascular disease in adulthood.

scholarly journals Helicobacter pylori; a Way to Gastric Cancer?

2021 ◽  
Author(s):  
Norma Sánchez-Zauco ◽  
Erandi Pérez-Figueroa ◽  
Carmen Maldonado-Bernal
Keyword(s):  
Gastric Cancer ◽  
Helicobacter Pylori ◽  
Inflammatory Responses ◽  
Salt Intake ◽  
Clinical Symptoms ◽  
Nucleotide Polymorphisms ◽  
Stomach Pain ◽  
High Salt Intake ◽  
Patient Prognosis ◽  
Development Of Gastric Cancer

Gastric cancer is one of the types of cancer that is associated with Helicobacter pylori infection. The infection starts in childhood, and 50–90% of the population in the world is infected. The clinical symptoms can be stomach pain, gastritis, atrophy gastric, and only 2–3% of the infected population developed gastric cancer. The majority of gastric cancers are adenocarcinomas. From Lauren’s histological classification, gastric cancer is divided into two large groups: intestinal and diffuse. The cells that gives rise to them are different and the epidemiologic features and diagnosis are different according to gender and age; however; the survival rate is approximately of 5-years. Surgery is the only radical treatment, but the adjuvant treatment is chemotherapy and radiotherapy which unfortunately lead to only a modest survival benefit. On this review, we describe the major risk factors associated with the bacteria: cagPAI, CagA, VacA, HOPs, as well as host immune and inflammatory responses: immune cells, Toll-like receptors, cytokines, immune signal pathway, genetic predisposition, such as single nucleotide polymorphisms (SNP’s) and environmental factors: age, high salt intake, diets low in fruit and vegetables, alcohol intake, and tobacco use. Finally, we included the interaction of all factors for the development of gastric cancer. Knowing and understanding the role of all factors in the development of gastric cancer will allow the implementation of better therapies and improve patient prognosis.

scholarly journals Chronic clofibrate administration prevents salineinduced endothelial dysfunction and oxidative stress in young Sprague-Dawley rats

2008 ◽  
Vol 31 (2) ◽  
pp. 62 ◽  
Author(s):  
Sowndramalingam Sankaralingam ◽  
Kaushik M Desai ◽  
Thomas W Wilson
Keyword(s):  
Oxidative Stress ◽  
Endothelial Dysfunction ◽  
Salt Intake ◽  
High Salt ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
High Salt Intake ◽  
Induced Hypertension ◽  
And Oxidative Stress ◽  
Hypotensive Response

Purpose: High salt intake causes hypertension and endothelial dysfunction in young Sprague-Dawley rats. Clofibrate (clof) prevents this salt induced hypertension. We asked whether clof can prevent salt-induced endothelial dysfunction, and if so, its mechanism. We also questioned whether high salt intake can induce endothelial dysfunction without hypertension in older animals. Methods: Young (Y, 5 weeks) and old (O, 53 weeks) male Sprague-Dawley rats were given either vehicle (Con, 20 mM Na2CO3) or 0.9% NaCl (Sal) to drink for three weeks. Some young rats received clof (80 mg/d) in their drinking fluid. After three weeks, we measured mean arterial pressure (MAP), endothelial function, by comparing hypotensive responses to acetylcholine (ACh, endothelium dependent) and sodium nitroprusside (SNP, endothelium independent), plasma total nitrite+nitrate levels (PNOx), by the Griess reaction, and aortic superoxide production by lucigenin chemiluminescence. Results: Carotid artery MAP did not change in O. Sal-Y developed hypertension: 133±3 vs. 114±2 mmHg, P < 0.001, which was prevented by clof: 105±2 mmHg. ACh induced a similar dose dependent hypotensive response in Con-O and Sal-O that was inhibited by L-NAME (100mg/kg i.v.). Responses to ACh were blunted in Sal-Y but not in Con-Y. Further, L-NAME inhibited ACh responses only in Con-Y. The response to SNP was similar in all animals. Importantly, the ACh-induced hypotensive response was potentiated in clof+Sal-Y, an effect which was attenuated by blocking calcium-activated potassium channels (KCa) with a combination of apamin (50 ug/kg i.v.) + charybdotoxin (50 ug/kg i.v.), but not by L-NAME. PNOx was reduced in Sal-Y compared to Con-Y (2.09±0.26 vs. 4.8±0.35 µM, P < 0.001), but not in Sal-O. Aortic superoxide production was higher (P < 0.001) in Sal-Y (2388±40 milliunits/mg/min) than Sal-O (1107±159 milliunits/mg/min), but was reduced by clof (1378±64 milliunits/mg/min; P < 0.001). Conclusions: High salt intake increases oxidative stress in young animals, leading to impaired nitric oxide activity and endothelial dysfunction. Clofibrate prevents endothelial dysfunction partly through reduced O2?- formation but mainly via selective activation of KCa channels. Older animals are resistant to both salt induced hypertension and oxidative stress.

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