The long term objective is to better understand corticosteroid mechanisms of regulation of ion transport in renal epithelia and ultimately to apply this knowledge in vivo to the study of Na+ and K+ metabolism in man in health and disease e.g. in states of excessive Na+ retention and in hypertension. This proposal deals with glucocorticoid regulation of Na+ and K+ transport in a line of cultured epithelia of renal origin (A6) exhibiting active Na+ transport (short-circuit current; Isc) which is stimulated by corticosterone and aldosterone. Corticosterone, which produces twice the Isc increase induced by aldosterone, may do so by a receptor mediated mechanism other than that shared with aldosterone. After 48h the enhanced effect of corticosterone down regulates and chronic exposure to the steroid produces morphologic change. One of the two nuclear bound metabolites of corticosterone (it's 6Beta-OH-derivative) stimulates active Na+ transport and may contribute to corticosterone's action. The proposal will focus on these newly described phenomena. Ion transport will be assessed with an """"""""inhood"""""""" short-circuiter and by ion flux measurements in Ussing chambers. Receptors will be evaluated by nuclear binding of 3H-steroids in situ. TLC and HPLC will be utilized for most corticosteroid metabolite studies.
The specific aims are: 1) Compare effects of corticosterone and 6Beta-OH-corticosterone on Na+ and K+ transport to alterations produced by aldosterone. 2) Determine if cortisol is metabolized to 6Beta-OH-cortisol and study their ion transport effects. 3) Establish whether corticosterone, cortisol and their 6Beta-OH-derivatives occupy nuclear binding sites other than those co-occupied with aldosterone and correlate binding of these and other steroids with ion transport stimulation. 4) Study the effect of alteration in corticosterone metabolism on its Na+ transport stimulation. 5) Test ACTH and other relevant polypeptide hormones as direct modulators of corticosterone action. 6) Determine in the rat whether the glucocorticoids and their 6Beta-OH-derivatives have effects on renal handling of Na+ not shared by aldosterone. 7) Further characterize the Isc down regulation and the associated morphologic changes and determine whether the two phenomena are causally related; assess the role of corticosterone metabolites and receptor regulation in this process. 8) Identify the other metabolite of corticosterone and test it for effects on ion transport.
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