The long-term goal of this project is to understand the interaction between aldosterone and endothelin-1 (ET-1) and the potential role of this interaction as a feedback system on renal sodium (Na) transport. Both hormones play a role in the pathogenesis of hypertension, cardiovascular fibrosis, and nephrosclerosis. Aldosterone acts on the distal nephron and collecting duct to increase Na reabsorption and blood pressure. Results from two recent clinical studies (RALES and EPHESUS) demonstrated that aldosterone blockade reduced morbidity and mortality even in patients already receiving angiotensin- converting enzyme-inhibitors and beta blockers. Clearly, understanding aldosterone action will provide important insight into several pathophysiological states. The classical mechanism of aldosterone involves stimulation of target gene expression through the mineralocorticoid receptor, and possibly the glucocorticoid receptor. In earlier work, we demonstrated that aldosterone stimulated transcription of the ET-1 gene in an inner medullary collecting duct (IMCD) cell line. In the present application we have validated this observation in both acutely isolated rat IMCD and in three additional collecting cell models in vitro. Renal ET-1 is known to stimulate natriuresis and diuresis. Collecting-duct specific ET-1 knockout mice exhibit salt- sensitive hypertension. Likewise, multiple studies have demonstrated that ET-1 inhibits the epithelial Na channel (ENaC). Thus, aldosterone and ET-1 exert opposing actions on renal Na transport, and by this mechanism, opposing actions on systemic blood pressure. This led us to hypothesize that aldosterone- induced ET-1 triggers a negative feedback mechanism to attenuate aldosterone-mediated Na reabsorption. The present application will characterize the induction of ET-1 by aldosterone in the kidney and the role of ET-1 in the regulation of renal Na transport. To demonstrate that this interaction occurs in the animal a series of dose-response and time course studies will examine ET-1 mRNA and protein levels in response to aldosterone. To demonstrate that the proposed feedback mechanism is functional in the animal we will examine aldosterone mediated Na transport in microperfused tubules from normal and collecting duct- specific ET-1 knockout mice. The result will be corroborated by determining Na transport in the presence of pharmacological inhibitors of ET-1 A and B receptors. We will also investigate the molecular mechanism of action of aldosterone on the ET-1 gene. The in vitro work will be extended by using DNase I hypersensitivity, chromatin immunoprecipitation, and DNA affinity purification assays to study the role of chromatin structure and transcription factor binding in the aldosterone-mediated regulation of ET-1. The results of these studies will provide valuable insight into how aldosterone and ET-1 interact to modulate Na homeostasis. Importantly, these studies will lend understanding into a novel signaling pathway that may explain the role of aldosterone in the progression of cardiovascular and renal disease.
Lay summary: Aldosterone is a very important hormone that controls blood pressure. We discovered several years ago that this hormone regulates certain genes very quickly in kidney cells, which suggests that these genes are important for the control of aldosterone's action. One of these genes that aldosterone stimulates is endothelin, a powerful vasoconstrictor of blood vessels. Within the kidney endothelin also promotes salt excretion by the kidney whereas aldosterone enhances kidney salt retention. This study will examine whether endothelin acts as a local inhibitory mechanism and feedback control system on the action of aldosterone.
|Welch, Amanda K; Jeanette Lynch, I; Gumz, Michelle L et al. (2016) Aldosterone alters the chromatin structure of the murine endothelin-1 gene. Life Sci 159:121-6|
|Lynch, I Jeanette; Welch, Amanda K; Gumz, Michelle L et al. (2015) Effect of mineralocorticoid treatment in mice with collecting duct-specific knockout of endothelin-1. Am J Physiol Renal Physiol 309:F1026-34|
|Jacobs, Mollie E; Jeffers, Lauren A; Welch, Amanda K et al. (2014) MicroRNA regulation of endothelin-1 mRNA in renal collecting duct cells. Life Sci 118:195-9|
|Richards, Jacob; Welch, Amanda K; Barilovits, Sarah J et al. (2014) Tissue-specific and time-dependent regulation of the endothelin axis by the circadian clock protein Per1. Life Sci 118:255-62|
|Jacobs, Mollie E; Wingo, Charles S; Cain, Brian D (2013) An emerging role for microRNA in the regulation of endothelin-1. Front Physiol 4:22|
|Lynch, I Jeanette; Welch, Amanda K; Kohan, Donald E et al. (2013) Endothelin-1 inhibits sodium reabsorption by ET(A) and ET(B) receptors in the mouse cortical collecting duct. Am J Physiol Renal Physiol 305:F568-73|
|Giebisch, Gerhard H; Wingo, Charles S (2013) Renal potassium homeostasis: a short historical perspective. Semin Nephrol 33:209-14|
|Welch, A K; Jacobs, M E; Wingo, C S et al. (2013) Early progress in epigenetic regulation of endothelin pathway genes. Br J Pharmacol 168:327-34|
|Stow, Lisa R; Richards, Jacob; Cheng, Kit-Yan et al. (2012) The circadian protein period 1 contributes to blood pressure control and coordinately regulates renal sodium transport genes. Hypertension 59:1151-6|
|Stow, Lisa R; Voren, George E; Gumz, Michelle L et al. (2012) Dexamethasone stimulates endothelin-1 gene expression in renal collecting duct cells. Steroids 77:360-6|
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