Na+ reabsorption in airway and alveolar epithelia is critically important at the time of birth and continues to play a significant role after birth and throughout life to regulate the ionic composition, and volume of pulmonary secretions. Immature or dysregulated Na+ and fluid reabsorption in the airway and alveoli may contribute to the pathophysiology of respiratory distress syndrome (RDS) of the newborn and of lung disorders that are characterized by excess airway liquid such as that seen in pulmonary edema or following a toxic, infectious or inflammatory lung injury. In this research plan we propose to study two important regulators of perinatal Na+ transport in the lung, cyclic AMP and glucocorticoids, focusing on the role of sgk1, a kinase that appears to be a point of convergence for many signaling pathways that stimulate Na+ transport. Our hypothesis is that cyclic AMP and GC, acting through sgk1 stimulate Na+ transport in distal lung epithelia and in fetal lung and that regulation of sgk1 expression occurs primarily at the level of sgk1 gene transcription. We will first investigate if cyclic AMP-and GC-regulated Na+ transport in human fetal lung and in fetal distal lung epithelial cells occurs, in part, through stimulation of sgk1. Na+ transport will be measured by short-circuit current in a distal lung epithelial cell line and amiloride-sensitive changes in lumen volume measured in human fetal lung. The role of sgk1 will be investigated by expression of dominant negative sgk1 or by antisense oligonucleotides. We will also test the hypothesis that adenoviral transfer of sgk1 can enhance cyclic AMP- and GC-mediated Na+ transport in distal lung epithelia and in fetal lung. Second, we will determine if elevation of cyclic AMP stimulates sgk1 expression in fetal lung and in distal lung epithelia and identify the pathways of regulation. The proposed experiments will measure sgk1 mRNA and protein; determine the mechanism of regulation in response to cyclic AMP stimulation and map pathways of regulation. Finally, we will identify the cyclic AMP-stimulated enhancer elements of the sgk1 gene in distal lung epithelia by transient transfection, gel mobility shift assays and by chromatin immunoprecipitation assays. Understanding the mechanisms of regulation of Na+ transport by hormone mediated events and second messenger systems offers the potential for modulating Na+ transport in respiratory epithelia in a variety of pathophysiological conditions including RDS.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Human Embryology and Development Subcommittee 1 (HED)
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Berberich, Mary Anne
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University of Iowa
Internal Medicine/Medicine
Schools of Medicine
Iowa City
United States
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Raikwar, Nandita S; Thomas, Christie P (2017) Aldosterone regulates a 5' variant sgk1 transcript via a shared hormone response element in the sgk1 5' regulatory region. Physiol Rep 5:
Raikwar, Nandita S; Liu, Kang Z; Thomas, Christie P (2012) A regulated NH2-terminal Sgk1 variant with enhanced function is expressed in the collecting duct. Am J Physiol Renal Physiol 303:F1527-33
Thomas, Christie P; Raikwar, Nandita S; Kelley, Elizabeth A et al. (2010) Alternate processing of Flt1 transcripts is directed by conserved cis-elements within an intronic region of FLT1 that reciprocally regulates splicing and polyadenylation. Nucleic Acids Res 38:5130-40
Raikwar, Nandita S; Vandewalle, Alain; Thomas, Christie P (2010) Nedd4-2 interacts with occludin to inhibit tight junction formation and enhance paracellular conductance in collecting duct epithelia. Am J Physiol Renal Physiol 299:F436-44
Thomas, Christie P; Andrews, Janet I; Raikwar, Nandita S et al. (2009) A recently evolved novel trophoblast-enriched secreted form of fms-like tyrosine kinase-1 variant is up-regulated in hypoxia and preeclampsia. J Clin Endocrinol Metab 94:2524-30
Raikwar, Nandita S; Snyder, Peter M; Thomas, Christie P (2008) An evolutionarily conserved N-terminal Sgk1 variant with enhanced stability and improved function. Am J Physiol Renal Physiol 295:F1440-8
Raikwar, Nandita S; Thomas, Christie P (2008) Nedd4-2 isoforms ubiquitinate individual epithelial sodium channel subunits and reduce surface expression and function of the epithelial sodium channel. Am J Physiol Renal Physiol 294:F1157-65
Thomas, Christie P; Andrews, Janet I; Liu, Kang Z (2007) Intronic polyadenylation signal sequences and alternate splicing generate human soluble Flt1 variants and regulate the abundance of soluble Flt1 in the placenta. FASEB J 21:3885-95
Thomas, Christie P; Liu, Kang Z; Vats, Hemender S (2006) Medroxyprogesterone acetate binds the glucocorticoid receptor to stimulate alpha-ENaC and sgk1 expression in renal collecting duct epithelia. Am J Physiol Renal Physiol 290:F306-12
Itani, Omar A; Stokes, John B; Thomas, Christie P (2005) Nedd4-2 isoforms differentially associate with ENaC and regulate its activity. Am J Physiol Renal Physiol 289:F334-46

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