Journal
STEROIDS
Volume 81, Issue -, Pages 43-48Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.steroids.2013.11.005
Keywords
Aldosterone; Kidney; Epithelial sodium channel; Protein kinase D
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Aldosterone regulates blood pressure through its effects on the kidney and the cardiovascular system. Dysregulation of aldosterone signalling can result in hypertension which in turn can lead to chronic pathologies of the kidney such as renal fibrosis and nephropathy. Aldosterone acts by binding to the mineralocorticoid receptor (MR), which acts as a ligand-dependent transcription factor in target tissues such as segments of the distal nephron including the connecting tubule and cortical collecting duct (CCD). Aldosterone also promotes the activation of protein kinase signalling cascades that are coupled to growth factor receptors and act directly on specific substrates in the cell membrane or cytoplasm. The rapid actions of aldosterone can also modulate gene expression through the phosphorylation of transcription factors. Aldosterone is a key regulator of Na+ conservation in the distal nephron, largely through multiple mechanisms that modulate the activity of the epithelial Na+ channel (ENaC). Aldosterone transcriptionally up-regulates the ENaC alpha subunit and also up regulates serum and glucocorticoid-regulated kinase-1 (SGK1) that indirectly regulates the ubiquitination of ENaC subunits. Aldosterone promotes the activation of protein kinase D1 (PKD1) which can modify the activity of ENaC and other transporters through effects on sub-cellular trafficking. In M1-CCD cells, early sub-cellular trafficking causes the redistribution of ENaC subunits within minutes of treatment with aldosterone. ENaC subunits can also interact directly with phosphatidylinositide signalling intermediates in the membrane and the mechanism by which PKD isoforms regulate protein trafficking is through the control of vesicle fission from the trans Golgi network by activation of phosphatidylinositol 4-kinaseIII beta (PI4KIII beta) (C) 2013 Elsevier Inc. All rights reserved.
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