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Human Mineralocorticoid Receptor Expression Renders Cells Responsive for Nongenotropic Aldosterone Actions

Physiologisches Institut der Universität Würzburg (C.G., A.B., R.F., S.M., B.G., M.G.), 97070 Würzburg, Germany; and Universitätsklinikum, Medical Clinic (A.W.K.), Technical University Dresden, 01062 Dresden, Germany

Address all correspondence and requests for reprints to: Prof. Dr. Med. Michael Gekle, Professor of Physiology, Physiologisches Institut, Universität Würzburg, Röntgenring 9, 97070 Würzburg, Germany. 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 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.

NURSA Molecule Pages Link:

Nuclear Receptors:   GR  |  MR

Ligands:   Dexamethasone  |  Spironolactone  |  Aldosterone

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