PubMed · 14413170
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P LABADIE. 1960. [Aldosterone].. https://pubmed.ncbi.nlm.nih.gov/14413170/
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The ability of aldosterone to stimulate Na+ transport in a range of epithelial tissues has been known for many years. Early work suggested that aldosterone had a delayed action operating by transcriptional up-regulation of proteins such as the epithelial Na+ channel. However more recent data has suggested that the hormone has a short-term non-genomic action. In this paper we investigate short and long-term actions of aldosterone on Na+ transport in the rabbit urinary bladder. We have shown that aldosterone stimulates epithelial Na+ channel activity, as measured by the amiloride-sensitive short-circuit current over a 3.75 h period and that this action is potentiated by cAMP. Using reverse transcriptase-polymerase chain reaction we have shown that aldosterone and forskolin in combination up-regulate mRNA synthesis for the beta- and gamma-subunits of the epithelial Na+ channel. Using Western blotting we have shown in the case of the beta-subunit that a corresponding increase in channel protein occurs. We have also demonstrated that aldosterone in the presence of inhibitors of phosphodiesterase can stimulate the short-circuit current across rabbit bladder epithelium over a 20 min period. An explanation for the synergistic interaction between aldosterone and cAMP is provided. We have shown that aldosterone can increase cAMP levels within urothelial cells over a 4 min period. We propose that this represents a non-genomic action of the steroid hormone.
The steroid hormone aldosterone is important for salt and water homeostasis as well as for pathological tissue modifications in the cardiovascular system and the kidney. The mechanisms of action include a classical genomic pathway, but physiological relevant nongenotropic effects have also been described. Unlike for estrogens or progesterone, the mechanisms for these nongenotropic effects are not well understood, although pharmacological studies suggest a role for the mineralocorticoid receptor (MR). Here we investigated whether the MR contributes to nongenotropic effects. After transfection with human MR, aldosterone induced a rapid and dose-dependent phosphorylation of ERK1/2 and c-Jun NH2-terminal kinase (JNK) 1/2 kinases in Chinese hamster ovary or human embryonic kidney cells, which was reduced by the MR-antagonist spironolactone and involved cSrc kinase as well as the epidermal growth factor receptor. In primary human aortic endothelial cells, similar results were obtained for ERK1/2 and JNK1/2. Inhibition of MAPK kinase (MEK) kinase but not of protein kinase C prevented the rapid action of aldosterone and also reduced aldosterone-induced transactivation, most probably due to impaired nuclear-cytoplasmic shuttling of MR. Cytosolic Ca2+ was increased by aldosterone in mock- and in human MR-transfected cells to the same extend due to Ca2+ influx, whereas dexamethasone had virtually no effect. Spironolactone did not prevent the Ca2+ response. We conclude that some nongenotropic effects of aldosterone are MR dependent and others are MR independent (e.g. Ca2+), indicating a higher degree of complexity of rapid aldosterone signaling. According to this model, we have to distinguish three aldosterone signaling pathways: 1) genomic via MR, 2) nongenotropic via MR, and 3) nongenotropic MR independent.
We investigated the coregulator (coactivator and corepressor) interactions with the mineralocorticoid receptor (MR) that lead to activation and inhibition of the receptor in the presence of agonist and/or antagonist. Our results indicate that MR ligand binding domain (LBD) interacts strongly with only a few specific coactivator peptides in the presence of the agonist aldosterone and that these interactions are blocked by the antagonist eplerenone. We also discovered that cortisol, the preferred physiological ligand for the glucocorticoid receptor in humans, is a partial MR agonist/antagonist, providing a possible molecular explanation of the tissue-selective effects of glucocorticoids on MR. However, when we examined the coactivator and corepressor peptide interactions in the presence of cortisol, we found that MR bound with cortisol or aldosterone interacted with the same set of peptides. Thus, the partial agonism shown by cortisol is unlikely to be the result of differential interaction with known coactivators and corepressors. On the other hand, we have identified coactivator binding groove mutations that are critical for cortisol activation but not for aldosterone activation, suggesting that the two steroids induce different MR LBD conformations. In addition, we also show that cortisol becomes full agonist when S810L mutation is introduced in the LBD of MR. Interestingly, MR antagonists, such as eplerenone and progesterone, become partial agonist/antagonist of S810L but are still able to recruit LXXLL peptides to the mutant receptor. Together, these findings suggest a model to explain the MR activation by various ligands.