Abstract
Aldosterone elicits transcriptional responses in target tissues and also rapidly stimulates the activation of protein kinase signalling cascades independently of de novo protein synthesis. Here we investigated aldosterone-induced cell proliferation and extra-cellular regulated kinase 1 and 2 (ERK1/2) mitogen activated protein (MAP) kinase signalling in the M1 cortical collecting duct cell line (M1-CCD). Aldosterone promoted the proliferative growth of M1-CCD cells, an effect that was protein kinase D1 (PKD1), PKCdelta and ERK1/2-dependent. Aldosterone induced the rapid activation of ERK1/2 with peaks of activation at 2 and 10 to 30 min after hormone treatment followed by sustained activation lasting beyond 120 min. M1-CCD cells suppressed in PKD1 expression exhibited only the early, transient peaks in ERK1/2 activation without the sustained phase. Aldosterone stimulated the physical association of PKD1 with ERK1/2 within 2 min of treatment. The mineralocorticoid receptor (MR) antagonist RU28318 inhibited the early and late phases of aldosterone-induced ERK1/2 activation, and also aldosterone-induced proliferative cell growth. Aldosterone induced the sub-cellular redistribution of ERK1/2 to the nuclei at 2 min and to cytoplasmic sites, proximal to the nuclei after 30 min. This sub-cellular distribution of ERK1/2 was inhibited in cells suppressed in the expression of PKD1.
Copyright 2009 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetophenones / pharmacology
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Active Transport, Cell Nucleus / drug effects
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Aldosterone / pharmacology*
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Animals
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Benzopyrans / pharmacology
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Cell Line
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Cell Proliferation / drug effects*
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Cytoplasm / metabolism
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Enzyme Activation
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Epithelial Cells / cytology
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Epithelial Cells / drug effects
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Epithelial Cells / metabolism*
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ErbB Receptors / antagonists & inhibitors
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ErbB Receptors / metabolism
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Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
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Extracellular Signal-Regulated MAP Kinases / metabolism*
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Flavonoids / pharmacology
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Kidney Cortex / cytology*
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Kidney Tubules, Collecting / cytology*
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Mice
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Mineralocorticoid Receptor Antagonists / pharmacology
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Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 3 / metabolism
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Models, Biological
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Phosphorylation / drug effects
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Protein Binding / drug effects
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Protein Kinase C-delta / antagonists & inhibitors
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Protein Kinase C-delta / metabolism
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Protein Kinase Inhibitors / pharmacology
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Quinazolines
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Receptors, Mineralocorticoid / metabolism
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Signal Transduction / drug effects
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Signal Transduction / physiology
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Spironolactone / analogs & derivatives
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Spironolactone / pharmacology
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TRPP Cation Channels / antagonists & inhibitors
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TRPP Cation Channels / genetics
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TRPP Cation Channels / metabolism*
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Tyrphostins / pharmacology
Substances
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Acetophenones
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Benzopyrans
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Flavonoids
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Mineralocorticoid Receptor Antagonists
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Protein Kinase Inhibitors
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Quinazolines
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Receptors, Mineralocorticoid
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TRPP Cation Channels
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Tyrphostins
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polycystic kidney disease 1 protein
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RTKI cpd
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Spironolactone
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Aldosterone
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RU 28318
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rottlerin
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ErbB Receptors
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Protein Kinase C-delta
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Extracellular Signal-Regulated MAP Kinases
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one