کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
1908587 1046672 2012 13 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Modulation of transcriptional mineralocorticoid receptor activity by nitrosative stress
موضوعات مرتبط
علوم زیستی و بیوفناوری بیوشیمی، ژنتیک و زیست شناسی مولکولی سالمندی
پیش نمایش صفحه اول مقاله
Modulation of transcriptional mineralocorticoid receptor activity by nitrosative stress
چکیده انگلیسی

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.

Graphical AbstractFigure optionsDownload high-quality image (283 K)Download as PowerPoint slideHighlights
► Nitrosative stress influences genomic corticosteroid receptor activity.
► NO reduces genomic mineralocorticoid (MR) and glucocorticoid receptor (GR) activity.
► Mechanistically, NO reduces corticosteroid receptor–DNA interaction.
► Peroxynitrite acts as a ligand-independent activator of MR but not of GR.
► Mechanistically, peroxynitrite enhances nuclear import of the MR.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Free Radical Biology and Medicine - Volume 53, Issue 5, 1 September 2012, Pages 1088–1100
نویسندگان
, , , , , , , ,