Modulation of transcriptional mineralocorticoid receptor activity by nitrosative stress.

Abstract

The mineralocorticoid receptor (MR) plays an important role in salt and water homeostasis and pathological tissue modifications, such as cardiovascular and renal fibrosis. Importantly, MR activation by aldosterone per se is not sufficient for the deleterious effects but requires the additional presence of a certain pathological milieu. Phenomenologically, this milieu could be generated by enhanced nitrosative stress. However, little is known regarding the modulation of MR transcriptional activity in a pathological milieu. The glucocorticoid receptor (GR), the closest relative of the MR, binds to the same hormone-response element but elicits protective effects on the cardiovascular system. To investigate the possible modulation of MR and GR by nitrosative stress under controlled conditions we used human embryonic kidney (HEK) cells and measured MR and GR transactivation after stimulation with the nitric oxide (NO)-donor SNAP and the peroxynitrite-donor Sin-1. In the presence of corticosteroids NO led to a general reduced corticosteroid receptor activity by repression of corticosteroid receptor-DNA interaction. The NO-induced diminished transcriptional MR activity was most pronounced during stimulation with physiological aldosterone concentrations, suggesting that NO treatment prevented its pathophysiological overactivation. In contrast, single peroxynitrite administration specifically induced the MR transactivation activity whereas genomic GR activity remained unchanged. Mechanistically, peroxynitrite permitted nuclear MR translocation whereas the cytosolic GR distribution was unaffected. Consequently, peroxynitrite represents a MR-specific aldosterone mimetic. In summary, our data indicate that the genomic function of corticosteroid receptors can be modulated by nitrosative stress which may induce the shift from physiological toward pathophysiological MR effects.

• Authors: Stefanie Ruhs, Nicole Strätz, Kathleen Schlör, Sandra Meinel, Sigrid Mildenberger, Sindy Rabe, Michael Gekle, Claudia Grossmann
• Journal: Free radical biology & medicine (Free Radic Biol Med) Vol. 53 Issue 5 Pg. 1088-100 (Sep 01 2012) ISSN: 1873-4596 [Electronic] United States
• PMID: 22749806 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical References

• Receptors, Glucocorticoid
• Receptors, Mineralocorticoid
• Nitric Oxide
• linsidomine
• S-Nitroso-N-Acetylpenicillamine
• Molsidomine

Topics

• Cells, Cultured
• HEK293 Cells
• Humans
• Molsidomine (analogs & derivatives, pharmacology)
• Nitric Oxide (metabolism)
• Oxidative Stress (drug effects)
• Receptors, Glucocorticoid (genetics, metabolism)
• Receptors, Mineralocorticoid (genetics, metabolism)
• S-Nitroso-N-Acetylpenicillamine (pharmacology)