The specific objective of this project is to study the effects of mineralocorticoids and glucocorticoids on sodium and potassium transport in primary cultures of cortical collecting tubule cells, in order to elucidate the actions and interactions of these corticosteroids at the cellular level, in particular the mechanisms that allow aldosterone to exert mineralocorticoid actions in the presence of high levels of glucocorticoids. Major questions on the regulation by corticosteroids of salt excretion have arisen from the recent observation that corticosterone and cortisol, both classic glucocorticoids, have affinities for the mineralocorticoid receptor similar to that of aldosterone, and from the discovery that the clinical syndrome of apparent mineralocorticoid excess is caused by defective degradation of cortisol. Clarification of the cellular mechanisms behind thee phenomena has been hampered by the complexity of available models. Recently, however, we have developed methods for isolating and culturing the two cell types of the cortical collecting tubule of the nephron, the major renal target of aldosterone. These cells maintain differentiated transport functions and hormonal responsiveness in culture, offering a unique model for study of underlying biochemical mechanisms. Using these cells, the effects of selected mineralocorticoids and glucocorticoids on Na+ ad K+ transport, the characteristics of the receptors through which these effects are exerted, and metabolism of corticosterone will be determined with the goal of answering two major questions: (1) What are the mechanisms that confer aldosterone selectivity in mineralocorticoid target cells despite the much higher circulating levels of corticosterone? (2) What is the function of the corticosterone-specific binding sites we have found in large numbers in cortical collecting tubule cells? The central hypothesis we will test is that in mineralocorticoid target cells, rapid metabolism of corticosterone coupled with the action of the abundant corticosterone binding sites, allows aldosterone to bind to mineralocorticoid receptors and exert its effect. We will test this hypothesis by simultaneous determination of the metabolism, intracellular free levels, effects on ion transport and binding of corticosterone and aldosterone. The new information acquired by these studies should help to clarify the mechanisms by which corticosteroids control Na+ and + transport in the distal nephron.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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General Medicine B Study Section (GMB)
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Dartmouth College
Schools of Medicine
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Latouche, Celine; Sainte-Marie, Yannis; Steenman, Marja et al. (2010) Molecular signature of mineralocorticoid receptor signaling in cardiomyocytes: from cultured cells to mouse heart. Endocrinology 151:4467-76
Naray-Fejes-Toth, Aniko; Boyd, Cary; Fejes-Toth, Geza (2008) Regulation of epithelial sodium transport by promyelocytic leukemia zinc finger protein. Am J Physiol Renal Physiol 295:F18-26
Martel, Jessica A; Michael, Donna; Fejes-Toth, Geza et al. (2007) Melanophilin, a novel aldosterone-induced gene in mouse cortical collecting duct cells. Am J Physiol Renal Physiol 293:F904-13
Boyd, Cary; Naray-Fejes-Toth, Aniko (2007) Steroid-mediated regulation of the epithelial sodium channel subunits in mammary epithelial cells. Endocrinology 148:3958-67
Naray-Fejes-Toth, Aniko; Fejes-Toth, Geza (2007) Novel mouse strain with Cre recombinase in 11beta-hydroxysteroid dehydrogenase-2-expressing cells. Am J Physiol Renal Physiol 292:F486-94
Cordas, Emily; Naray-Fejes-Toth, Aniko; Fejes-Toth, Geza (2007) Subcellular location of serum- and glucocorticoid-induced kinase-1 in renal and mammary epithelial cells. Am J Physiol Cell Physiol 292:C1971-81
Fejes-Toth, Geza; Naray-Fejes-Toth, Aniko (2007) Early aldosterone-regulated genes in cardiomyocytes: clues to cardiac remodeling? Endocrinology 148:1502-10
Atanasov, Atanas G; Nashev, Lyubomir G; Tam, Steven et al. (2005) Organotins disrupt the 11beta-hydroxysteroid dehydrogenase type 2-dependent local inactivation of glucocorticoids. Environ Health Perspect 113:1600-6
Boyd, Cary; Naray-Fejes-Toth, Aniko (2005) Gene regulation of ENaC subunits by serum- and glucocorticoid-inducible kinase-1. Am J Physiol Renal Physiol 288:F505-12
Naray-Fejes-Toth, Aniko; Helms, My N; Stokes, John B et al. (2004) Regulation of sodium transport in mammalian collecting duct cells by aldosterone-induced kinase, SGK1: structure/function studies. Mol Cell Endocrinol 217:197-202

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