Abstract
Aldosterone and endothelin-1 (ET-1) act on collecting duct cells of the kidney and are important regulators of renal sodium transport and cardiovascular physiology. We recently identified the ET-1 gene (edn1) as a novel aldosterone-induced transcript. However, aldosterone action on edn1 has not been characterized at the present time. In this report, we show that aldosterone stimulated edn1 mRNA in acutely isolated rat inner medullary collecting duct cells ex vivo and ET-1 peptide in rat inner medulla in vivo. Aldosterone induction of edn1 mRNA occurred in cortical, outer medullary, and inner medullary collecting duct cells in vitro. Inspection of the edn1 promoter revealed two putative hormone response elements. Levels of heterogeneous nuclear RNA synthesis demonstrated that edn1 mRNA stimulation occurred at the level of transcription. RNA knockdowns corroborated pharmacological studies and demonstrated both mineralocorticoid receptor and glucocorticoid receptor participated in this response. Aldosterone resulted in dose-dependent nuclear translocation and binding of mineralocorticoid receptor and glucocorticoid receptor to the edn1 hormone response elements. Hormone receptors mediated the association of chromatin remodeling complexes, histone modification, and RNA polymerase II at the edn1 promoter. Direct interaction between aldosterone and ET-1 has important implications for renal and cardiovascular function.
Highlights
The steroid hormone aldosterone is critical for sodium homeostasis and blood pressure control
We show that aldosterone stimulated edn1 mRNA in acutely isolated rat inner medullary collecting duct cells ex vivo and ET-1 peptide in rat inner medulla in vivo
Aldosterone Modulates Hormone Receptor Binding to the Edn1 Promoter—The observation that both mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) were involved in aldosterone-mediated edn1 transcription suggested that the edn1 promoter contained functional hormone response elements (HREs)
Summary
The steroid hormone aldosterone is critical for sodium homeostasis and blood pressure control. A typical HRE for MR consists of two receptor binding half-sites with the consensus sequence 5Ј-TGTTCT3Ј, arranged as an inverted palindrome [1, 5]. Aldosterone-responsive cells are protected from glucocorticoids by the activity of 11-hydroxysteroid dehydrogenase type 2, an enzyme that converts glucocorticoids into 11-ketosteroids that have very little affinity for MR or other steroid receptors [10, 11]. We identified endothelin-1 (edn1) as a transcript and protein that increases in response to aldosterone in inner medullary collecting duct (mIMCD-3) cells [19]. This hnRNA, heterogeneous nuclear RNA; siRNA, small interference RNA; DAPA, DNA-affinity purification analysis
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