Mechanism and function of aldosterone induction of endothelin-1 in renal collecting duct cells

This dissertation will focus on the function and mechanism of interaction between two hormones that regulate renal sodium transport; aldosterone and endothelin-1 (ET-1). Data presented in this work demonstrate that the ET-1 peptide was stimulated by aldosterone in rat inner medulla in vivo and the ET-1 gene (edn1) was stimulated by aldosterone in acutely isolated rat inner medullary collecting duct cells ex vivo and in mouse cortical, outer medullary, and inner medullary collecting duct cells in vitro. Mechanistic studies revealed that aldosterone directed the transcription of the edn1 promoter through two hormone response elements that bound both the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). These hormone receptors mediated the association of chromatin remodeling complexes, histone modification, and RNA polymerase II at the edn1 promoter. A synthetic glucocorticoid was able to replicate aldosterone action on edn1 through the exclusive action of GR. Preliminary functional studies indicated that edn1 knockdown altered normal mRNA expression patterns for two aldosterone response genes, sgk1 and scnn1a. Direct interaction between aldosterone and ET-1 has important implications for renal and cardiovascular function. (Full text of this dissertation may be available via the University of Florida Libraries web site. Please check http://www.uflib.ufl.edu/etd.html)...