Activation of mineralocorticoid receptors by exogenous glucocorticoids and the development of cardiovascular inflammatory responses in adrenalectomized rats

Morag J. Young, James Morgan, Kim Brolin, Peter J. Fuller, John W. Funder

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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 for8das follows: control; 20mgdeoxycorticosterone (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.

Original languageEnglish
Pages (from-to)2622-2628
Number of pages7
JournalEndocrinology
Volume151
Issue number6
DOIs
Publication statusPublished - Jun 2010
Externally publishedYes

Cite this

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title = "Activation of mineralocorticoid receptors by exogenous glucocorticoids and the development of cardiovascular inflammatory responses in adrenalectomized rats",
abstract = "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 for8das follows: control; 20mgdeoxycorticosterone (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.",
author = "Young, {Morag J.} and James Morgan and Kim Brolin and Fuller, {Peter J.} and Funder, {John W.}",
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Activation of mineralocorticoid receptors by exogenous glucocorticoids and the development of cardiovascular inflammatory responses in adrenalectomized rats. / Young, Morag J.; Morgan, James; Brolin, Kim; Fuller, Peter J.; Funder, John W.

In: Endocrinology, Vol. 151, No. 6, 06.2010, p. 2622-2628.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Activation of mineralocorticoid receptors by exogenous glucocorticoids and the development of cardiovascular inflammatory responses in adrenalectomized rats

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AU - Morgan, James

AU - Brolin, Kim

AU - Fuller, Peter J.

AU - Funder, John W.

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AB - 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 for8das follows: control; 20mgdeoxycorticosterone (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.

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