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Submitted on November 19, 2004
Accepted on March 3, 2005
Physiologisches Institut der Universität Würzburg, Würzburg, Germany, Universitätsklinikum, Medical Clinic III, Technical University Dresden, Dresden, Germany, = these authors contributed equally to this study and should be considered as first authors
* To whom correspondence should be addressed. E-mail: michael.gekle{at}mail.uni-wuerzburg.de.
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 JNK1/2 kinases in CHO- or HEK cells, which was reduced by the MR-antagonist spironolactone and involved cSrc-kinase as well as the EGF-receptor (EGFR). In primary human aortic endothelial cells similar results were obtained for ERK1/2 and JNK1/2. Inhibition of 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 hMR-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: (i) genomic via MR, (ii) nongenotropic via MR and (iii) nongenotropic MR-independent.
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