Question: 

The mineralocorticoid (MR) and glucocorticoid receptor (GR) belong to the steroid receptor family. Both act as ligand-inducible transcription factors which upon activation bind at the glucocorticoid hormone response element (GRE) in the promoter of genes. Although they bind to the same GREs, these receptors mediate different effectsin vivo. The MR regulates water and salt balance whereas GR mediates metabolic homeostasis and anti-inflammatory actions. Independently of its classical effects the activated MR promotes pathological tissue modifications, like cardiovascular and renal fibrosis. One hypothesis is that deleterious MR effects emerge only under pathological conditions with altered micro milieu conditions.

Methods: 

In this study we investigated the putative influence of nitrosative stress on MR and GR transactivation activity in a heterologous HEK cell expression system utilizing SNAP as a nitric oxide (NO) and Sin-1 as a peroxynitrite donor.

Results: 

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 hMR activity was most pronounced during stimulation with physiological aldosterone concentrations suggesting that NO may prevent its pathophysiological overactivation. In contrast, single peroxynitrite administration specifically induced the transactivation activity of hMR whereas genomic hGR activity remained unchanged. Mechanistically, peroxynitrite permitted the nuclear hMR translocation whereas the cytosolic hGR distribution was unaffected. Consequently, peroxynitrite represents an hMR-specific aldosterone mimetic.

Conclusion: 

Overall, our data indicate that the genomic function of corticosteroid receptors can be modulated by nitrosative stress which may induce the shift from physiological towards pathophysiological hMR effects.