Corticosterone-activated mineralocorticoid receptor contributes to salt-induced sympathoexcitation in pressure overload mice.
Abstract We previously reported that pressure overload (PO) activates the hypothalamic mineralocorticoid receptor (MR) and angiotensin II type 1 receptor (AT1R). Moreover, salt intake further activates the hypothalamic MR and AT1R, resulting in salt-induced sympathoexcitation. However, the mechanism underlying this pathway activation in response to a high salt intake remains unknown. Although the role of aldosterone is extensively examined as a ligand for MR, corticosterone is able to bind to MR. Therefore, we hypothesized that corticosterone contributes to salt-induced sympathoexcitation in PO-mice. Four weeks after aortic banding to produce PO-mice, or a sham operation for controls, the mice were fed a high-salt diet for an additional 4 weeks. Compared to Sham-mice, the expression levels of hypothalamic MR, serum glucocorticoid-induced kinase 1 (a marker of MR activity) and AT1R increased in PO-mice. Salt intake further increased the expression levels of these proteins only in PO-mice with the increases in sympathetic activity evaluated on the basis of the excretion of 24-h urinary norepinephrine excretion. Bilateral adrenalectomy or the intraperitoneal infusion of metyrapone, a corticosterone synthase inhibitor, attenuated salt-induced sympathoexcitation via inhibition of the hypothalamic MR and AT1R activity. These adrenalectomy-induced alterations disappeared after corticosterone replacement therapy. We also found decreased expression levels of 11β-hydroxysteroid dehydrogenase type 2, suggesting that corticosterone is apt to bind to MR. These results indicate that salt intake in PO-mice causes sympathoexcitation via, at least in part, corticosterone-induced MR and AT1R activation in the hypothalamus.
Department of Cardiovascular Medicine and.
Koji
K
Ito
Yoshitaka
Y
Hirooka
Kenji
K
Sunagawa
D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000378:metabolism; D000315:Adrenalectomy; D000450:Aldosterone / Q000097:blood; D000818:Animals; D003345:Corticosterone / Q000097:blood / Q000378:metabolism*; D006973:Hypertension / Q000209:etiology* / Q000378:metabolism*; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D017874:Immediate-Early Proteins / Q000378:metabolism; D008297:Male; D008797:Metyrapone / Q000494:pharmacology; D051379:Mice; D008813:Mice, Inbred ICR; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000378:metabolism*; D017673:Sodium Chloride, Dietary / Q000009:adverse effects; D013564:Sympathetic Nervous System / Q000378:metabolism; D000099184:Serum-Glucocorticoid Regulated Kinases
D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D000450:Aldosterone; D003345:Corticosterone; D017874:Immediate-Early Proteins; D008797:Metyrapone; D017346:Protein Serine-Threonine Kinases; D044140:Receptor, Angiotensin, Type 1; D018161:Receptors, Mineralocorticoid; D017673:Sodium Chloride, Dietary; D000099184:Serum-Glucocorticoid Regulated Kinases
Brain; heart failure; mineralocorticoid receptor; salt; sympathetic nervous system