Mineralocorticoid receptor antagonists do not block rapid ERK activation by aldosterone.
Aldosterone can elicit rapid nongenomic effects both in vivo and in vitro, often mediated by signal transduction cascades. However, it is not understood how these rapid effects are initiated. In this study we show that aldosterone leads to rapid activation of mitogen activated protein kinases ERK1/2 in the cortical collecting duct cell line M-1. Inhibitors of transcription and translation could not block this activation, which suggests an extranuclear (nongenomic) mechanism. Although it is known that M-1 cells do not contain a transcriptionally functional MR, it is not known whether a closely related protein still could mediate the effects, or an unrelated nonclassic receptor. To test this hypothesis, the effects of four classical mineralocorticoid receptor antagonists were studied. None of the compounds could block the response to aldosterone. Altogether, the data suggest that rapid aldosterone effects in M-1 cells are initiated by a receptor different from the classical mineralocorticoid receptor.
Rossol-Haseroth
Karin
K
Department of Clinical Pharmacology, Faculty of Clinical Medicine Mannheim, University of Heidelberg, 68167 Mannheim, Germany.
Zhou
Qian
Q
Braun
Sabine
S
Boldyreff
Brigitte
B
Falkenstein
Elisabeth
E
Wehling
Martin
M
Lösel
Ralf M
RM
D000450:Aldosterone / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D002460:Cell Line; D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D006854:Hydrocortisone / Q000494:pharmacology; D007672:Kidney Cortex / Q000166:cytology / Q000378:metabolism; D007685:Kidney Tubules, Collecting / Q000166:cytology; D051379:Mice; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism
D002070:Butadienes; D004791:Enzyme Inhibitors; D005419:Flavonoids; D000451:Mineralocorticoid Receptor Antagonists; D009570:Nitriles; C113580:U 0126; D003609:Dactinomycin; D000450:Aldosterone; D003513:Cycloheximide; D019908:Proto-Oncogene Proteins c-raf; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D006854:Hydrocortisone