Maintenance of extrecellular fluid volume homeostasis is essential for hemodynamic stability, and abnormalities of renal sodium handling have been linked to cardiovascular disease and hypertension. Ultimate regulation of sodium excretion occurs in the distal nephron via conductive transport through the amiloride sensitive epithelial Na+ channel (ENaC). ENaC expression and activity in the apical membrane of epithelial cells is the rate limiting step in Na+ reabsorption not only in the kidney collecting duct, but in airway epithelia and colon as well. Aldosterone is the major regulator of ENaC expression and activity in responsive epithelia. The long term objectives of this research are to define the mechanisms through which mineralocorticoid hormones regulate vectorial sodium transport in responsive epithelia and studies are designed to examine the mechanisms of aldosterone regulation of ENaC. Work in the current grant period has identified a specific methyltransferase which activates ENaC and knockdown of this protein blocks the early aldosterone response. Studies are now proposed to determine if this protein is required for early aldosterone action via genomic or non-genomic pathways and determine how aldosterone regulates its activity. We have demonstrated that ENaC trafficks to the apical membrane of epithelial cells in lipid rafts and developed a model of ENaC trafficking in cultured epithelial cells. Cells deprived of aldosterone develop a loss of Na+ reabsorptive activity along with a loss of the cellular recycling compartment for ENaC. The recycling compartment and Na+ reabsorptive phenotype are restored over time by aldosterone. Restoration of the ENaC recycling pathway is associated with adlosterone up-regulation of multiple proteins in the endosomal compartment. We will examine the mechanisms by which aldosterone regulates the apical expression of ENaC from endosomal and/or recycling pathways and determine what specific aldosterone-regulated proteins control the activity and expression of ENaC in endosomes and exocyst compartments to support apical translocation of ENaC in Na+ reabsorptive states.

Public Health Relevance

Aldosterone is the major hormone which regulates sodium reabsorption in the kidney in mammals. Abnormalities of sodium handling can lead to diseases such as hypertension and heart failure and have been implicated in the progression of cystic fibrosis lung disease. These studies are designed to determine the cellular mechanisms by which aldosterone regulates sodium reabsorption in kidney cells.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Cellular and Molecular Biology of the Kidney Study Section (CMBK)
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Ketchum, Christian J
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University of Pittsburgh
Internal Medicine/Medicine
Schools of Medicine
United States
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Edinger, Robert S; Coronnello, Claudia; Bodnar, Andrew J et al. (2014) Aldosterone regulates microRNAs in the cortical collecting duct to alter sodium transport. J Am Soc Nephrol 25:2445-57
Weixel, Kelly M; Marciszyn, Allison; Alzamora, Rodrigo et al. (2013) Resveratrol inhibits the epithelial sodium channel via phopshoinositides and AMP-activated protein kinase in kidney collecting duct cells. PLoS One 8:e78019
Argyropoulos, Christos; Wang, Kai; McClarty, Sara et al. (2013) Urinary microRNA profiling in the nephropathy of type 1 diabetes. PLoS One 8:e54662
Butterworth, Michael B; Edinger, Robert S; Silvis, Mark R et al. (2012) Rab11b regulates the trafficking and recycling of the epithelial sodium channel (ENaC). Am J Physiol Renal Physiol 302:F581-90
Edinger, Robert S; Bertrand, Carol A; Rondandino, Christine et al. (2012) The epithelial sodium channel (ENaC) establishes a trafficking vesicle pool responsible for its regulation. PLoS One 7:e46593
Edinger, Robert S; Lebowitz, Jonathan; Li, Hui et al. (2009) Functional regulation of the epithelial Na+ channel by IkappaB kinase-beta occurs via phosphorylation of the ubiquitin ligase Nedd4-2. J Biol Chem 284:150-7
Hallows, Kenneth R; Wang, Huamin; Edinger, Robert S et al. (2009) Regulation of epithelial Na+ transport by soluble adenylyl cyclase in kidney collecting duct cells. J Biol Chem 284:5774-83
Weixel, Kelly M; Edinger, Robert S; Kester, Lauren et al. (2007) Phosphatidylinositol 4-phosphate 5-kinase reduces cell surface expression of the epithelial sodium channel (ENaC) in cultured collecting duct cells. J Biol Chem 282:36534-42
Butterworth, Michael B; Edinger, Robert S; Ovaa, Huib et al. (2007) The deubiquitinating enzyme UCH-L3 regulates the apical membrane recycling of the epithelial sodium channel. J Biol Chem 282:37885-93
Hill, Warren G; Butterworth, Michael B; Wang, Huamin et al. (2007) The epithelial sodium channel (ENaC) traffics to apical membrane in lipid rafts in mouse cortical collecting duct cells. J Biol Chem 282:37402-11

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