Mineralocorticoid receptor antagonists do not block rapid ERK activation by aldosterone
Section snippets
Materials and methods
Materials. Aldosterone was purchased from Fluka (Buchs, Switzerland), ethanol was obtained from Merck (Darmstadt, Germany), and actinomycin, cycloheximide, canreonate, spironolactone, and RU 38486 (mifepristone) were from Sigma (Taufkirchen, Germany). MEK inhibitors PD98059 and U0126 were from Cell Signaling Technology (Frankfurt, Germany). Cell culture media and reagents were from Invitrogen (Karlsruhe, Germany). RU 26752 and RU 28318 were kindly provided by Hoechst (now Aventis,
ERK1/2 phosphorylation
By using a specific antibody which recognizes the active, phosphorylated forms of MAPK ERK1/2, we analyzed the activation of ERK1/2 in M-1 cells after treatment with aldosterone by Western immunoblot. To ensure equal loading of samples, an antibody that recognizes both the phosphorylated and non-phosphorylated forms of ERK1/2 was used.
Preliminary time course experiments revealed a maximum effect of aldosterone after 5 min which decreased after 10 min; no effect at all was seen in the time
Discussion
In this study we have demonstrated that the rapid activation of the ERK1/2 MAPK cascade in M-1 cells is not significantly inhibited by a structurally diverse set of antagonists at the classic mineralocorticoid receptor. The cell line used in these studies is derived from murine kidney cortical collecting duct, resembling principal cells which belong to the main targets for aldosterone [19]. In this cell line other rapid aldosterone effects (e.g., increases in intracellular Ca2+ levels, pH, and
Acknowledgements
This work was supported by a grant from the Deutsche Forschungsgemeinschaft (DFG We 1184/9-1). Parts of this work were done in the course of MD thesis preparation by Q.Z. The expert technical skills of Martina Seyfert are gratefully acknowledged.
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2022, Molecular and Cellular EndocrinologySignaling pathways involved in the rapid biphasic effect of aldosterone on Na<sup>+</sup>/H<sup>+</sup> exchanger in rat proximal tubule cells
2018, Journal of Steroid Biochemistry and Molecular BiologyCitation Excerpt :In addition, the rapid action of Aldo, coupled with insensitivity to actinomycin and cycloheximide, indicate a nongenomic signaling pathway for Aldo in IRPTC cells. These data are in accordance with previous studies in proximal tubule [4,6], medullary thick ascending limb [16], or cell line derived from the cortical collecting (M-1 cell) [29], where the acute effects of Aldo were independent of transcription and translation, suggesting a nongenomic mechanism. Our present results indicate that eplerenone alone or plus Aldo (10−12 and at 10−6 M) did not affect the NHE1 activity and [Ca2+]i levels.
Aldosterone-induced protein kinase signalling and the control of electrolyte balance
2018, SteroidsCitation Excerpt :The activation of PKCα by direct binding of aldosterone to the kinase has been demonstrated in vitro [132]. The existence of alternative aldosterone receptors has been proposed on the basis of the ineffectiveness of MR antagonism in blocking some responses or the detection of aldosterone in MR-knock out cells [133,134] PKCδ and PKCε isoforms can also be rapidly activated in response to aldosterone, however, this is not reliant on the direct binding of the hormone to the kinase but is coupled to MR through EGFR [118]. PKD1 activation follows a similar pattern [76] and has been implicated in the induction of proliferation in M1-CCD cells following aldosterone treatment [125] as well as in the stimulation of hypertrophy in cardiac myocytes [78].
Cardiac effects of aldosterone: Does gender matter?
2014, SteroidsCitation Excerpt :Genomic regulation by aldosterone is mediated when ligated MR interacts with protein co-regulators; the hormone–receptor complex then translocates to the nucleus and modulates transcription of various target genes [17]. The rapid extranuclear, non-genomic effects of aldosterone are not dependent on transcription and protein synthesis [18–21] and mediated through MR-dependent and MR-independent mechanisms [22–26], some of which are mediated via the G protein-coupled receptor 30 (GPR-30 or GPER) [27,28]. Adverse cardiac effects of elevated plasma levels of aldosterone, in combination with high-salt intake include hypertrophy [29,30], inflammation and fibrosis [14,15,31,32], left ventricular remodelling post-MI [33,34], apoptosis [16] and heart failure [35].
Mineralocorticoid receptor signaling: Crosstalk with membrane receptors and other modulators
2014, SteroidsCitation Excerpt :Their results indicate that inhibition of histone deacetylases diminishes MR transcription activity and thereby prevents development of hypertension [122]. Besides being affected by the micromilieu and by posttranslational modifications, MR signaling can also be modulated by cytosolic signaling components like mitogen activated protein kinases (MAPK), protein kinase C (PKC) and secondary messengers like calcium and cyclic adenosine monophosphate (cAMP)/cAMP response binding protein (CREB) [5,111,123–130], which has already been reviewed elsewhere [131]. Overall, there are still questions regarding MR signaling that have not been solved, yet.