ru-28318 and rottlerin

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.

Topics: Acetophenones; Active Transport, Cell Nucleus; Aldosterone; Animals; Benzopyrans; Cell Line; Cell Proliferation; Cytoplasm; Enzyme Activation; Epithelial Cells; ErbB Receptors; Extracellular Signal-Regulated MAP Kinases; Flavonoids; Kidney Cortex; Kidney Tubules, Collecting; Mice; Mineralocorticoid Receptor Antagonists; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Models, Biological; Phosphorylation; Protein Binding; Protein Kinase C-delta; Protein Kinase Inhibitors; Quinazolines; Receptors, Mineralocorticoid; Signal Transduction; Spironolactone; TRPP Cation Channels; Tyrphostins