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      Early Aldosterone Effects

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          Abstract

          Aldosterone stimulates sodium reabsorption across tight epithelia via corticosteroid receptors. These receptors are ligand-activated transcription factors which regulate a set of genes, leading to changes in the expression of proteins which are thought to mediate the stimulatory action on sodium reabsorption. This functional response starts after a lag period and can be schematically divided into an early phase of activation and a late phase of accumulation of effectors such as Na<sup>+</sup> channels and pumps. Recently, the first gene products regulated sufficiently rapidly by aldosterone to possibly account for the early activation have been identified. However, the actual mediators of the physiological response remain to be determined. Besides these transcriptionally mediated effects, aldosterone has been shown to produce rapid, nongenomic actions on intracellular signalling cascades leading to an activation of Na<sup>+</sup>/H<sup>+</sup> exchange. Such effects are mediated by a different type of receptor and have been described both in classical aldosterone target cells and other cells. Their physiological implications are as yet not clear. The aim of this minireview is to describe briefly both the classical early and rapid nongenomic effects of aldosterone and to address the question whether nongenomic effects might play a role for the Na<sup>+</sup> transport response.

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          Most cited references 7

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          Specific, nongenomic actions of steroid hormones.

           M Wehling (1996)
          Traditionally, steroid hormone action has been described as the modulation of nuclear transcription, thus triggering genomic events that are responsible for physiological effects. Despite early observations of rapid steroid effects that were incompatible with this theory, nongenomic steroid action has been widely recognized only recently. Evidence for these rapid effects is available for steroids of all clones and for a multitude of species and tissues. Examples of nongenomic steroid action include rapid aldosterone effects in lymphocytes and vascular smooth muscle cells, vitamin D3 effects in epithelial cells, progesterone action in human sperm, neurosteroid effects on neuronal function, and vascular effects of estrogens. Mechanisms of action are being studied with regard to signal perception and transduction, and researchers have developed a patchy sketch of a membrane receptor-second messenger cascade similar to those involved in catecholamine and peptide hormone action. Many of these effects appear to involve phospholipase C, phosphoinositide turnover, intracellular pH and calcium, protein kinase C, and tyrosine kinases. The physiological and pathophysiological relevance of these effects is unclear, but rapid steroid effects on cardiovascular, central nervous, and reproductive functions may occur in vivo. The cloning of the cDNA for the first membrane receptor for steroids should be achieved in the near future, and the physiological and clinical relevance of these rapid steroid effects can then be established.
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            Glucocorticoid and mineralocorticoid receptors: biology and clinical relevance.

             John Funder (1996)
            Mineralocorticoid and glucocorticoid receptors act as homodimers via canonical pentadecamer hormone response elements to regulate transcription. Glucocorticoid, but as yet not mineralocorticoid, receptors have been shown also to modulate AP-1- and NF kappa B-induced transcription by direct protein-protein interactions. The role of 11 beta-hydroxysteroid dehydrogenase in conferring aldosterone specificity on epithelial mineralocorticoid receptors has been proven by the demonstration of sequence mutations in all cases of apparent mineralocorticoid excess examined to date. The autosomal form of aldosterone resistance (pseudohypoaldosteronism) has been shown to reflect loss-of-function mutations in epithelial sodium channel subunit sequence. (Patho)physiological roles for aldosterone and glucocorticoid membrane receptors, and for the recently described nuclear receptors for 11-ketosteroids in 11 beta-hydroxysteroid dehydro-genase-protected epithelia, remain to be established.
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              Rapid activation of Na+/H+ exchange by aldosterone in renal epithelial cells requires Ca2+ and stimulation of a plasma membrane proton conductance.

              There is increasing evidence for an additional acute, nongenomic action of the mineralocorticoid hormone aldosterone on renal epithelial cells, leading to a two-step model of mineralocorticoid action on electrolyte excretion. We investigated the acute effect of aldosterone on intracellular free Ca2+ and on intracellular pH in an aldosterone-sensitive Madin-Darby canine kidney cell clone. Within seconds of application of aldosterone, but not of the glucocorticoid hydrocortisone, there was a 3-fold sustained increase of intracellular Ca2+ at a half-maximal concentration of 10(-10) mol/liter. Omission of extracellular Ca2+ prevented this hormone response. In the presence of extracellular Ca2+ aldosterone led to intracellular alkalinization. The Na+/H+ exchange inhibitor ethyl-isopropanol-amiloride (EIPA) prevented the aldosterone-induced alkalinization but not the aldosterone-induced increase of intracellular Ca2+. Omission of extracellular Ca2+ also prevented aldosterone-induced alkalinization. Instead, aldosterone led to a Zn(2+)-dependent intracellular acidification in the presence of EIPA, indicative of an increase of plasma membrane proton conductance. Under control conditions, Zn2+ prevented the aldosterone-induced alkalinization completely. We conclude that aldosterone stimulated net-entry of Ca2+ from the extracellular compartment and a plasma membrane H+ conductance as prerequisites for the stimulation of plasma membrane Na+/H+ exchange which in turn modulates K+ channel acitivity. It is probable that the aldosterone-sensitive H+ conductance maintains Na+/H+ exchange activity by providing an acidic environment in the vicinity of the exchanger. Thus, genomic action of aldosterone determines cellular transport equipment, whereas the nongenomic action regulates transporter activity that requires responses within seconds or minutes, which explains the rapid effects on electrolyte excretion.
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                Author and article information

                Journal
                EXN
                Nephron Exp Nephrol
                10.1159/issn.1660-2129
                Cardiorenal Medicine
                S. Karger AG
                1660-2129
                1998
                August 1998
                15 July 1998
                : 6
                : 4
                : 294-301
                Affiliations
                Institute of Physiology, University of Zürich, Switzerland
                Article
                20536 Exp Nephrol 1998;6:294–301
                10.1159/000020536
                © 1998 S. Karger AG, Basel

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                Pages: 8
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                Self URI (application/pdf): https://www.karger.com/Article/Pdf/20536
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