Induction of the epithelial Na+ channel via glucocorticoids in mineralocorticoid receptor knockout mice

Schulz-Baldes, Annette; Berger, Stefan; Grahammer, Florian; Warth, Richard; Goldschmidt, Imeke; Peters, J; Schütz, Günther; Greger, R.; Bleich, Markus

doi:10.1007/s004240100694

Cited by 45 publications

(27 citation statements)

References 40 publications

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“…The observation that the level of the mRNA coding for one ENaC subunit can be increased by glucocorticoid in the kidney is consistent with the recent demonstration that glucocorticoid treatment was able to increase the mRNA abundance for the three subunits of ENaC and to stimulate Na ϩ transport in isolated CCD and colon epithelium from MR knockout mice (32) and with absence of changes in the ENaC subunit transcripts in MR knockout mice (9). In the near future, the relative role of mineralocorticoid and glucocorticoid in triggering the Na/K response via MR and/or GR should be studied in nephron segment-specific (i.e., CCD) knockout animals using the Crelox technology (33), allowing a much more precise evaluation of their respective physiologic roles in sodium balance and homeostasis.…”

Section: Discussionsupporting

confidence: 90%

Mineralocorticoid Effects in the Kidney

Müller¹,

Парнова²,

Centeno³

et al. 2003

Journal of the American Society of Nephrology

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Abstract. Aldosterone exerts its effects through interactions with two types of binding sites, the mineralocorticoid (MR) and the glucocorticoid (GR) receptors. Although both receptors are known to be involved in the anti-natriuretic response to aldosterone, the mechanisms of signal transduction leading to modulation of electrolyte transport are not yet fully understood. This study measured the Na ϩ and K ϩ urinary excretion and the mRNA levels of three known aldosterone-induced transcripts, the serum and glucocorticoid-induced kinase (Sgk-1), the ␣ subunit of the epithelial Na ϩ channel (␣ENaC), and the glucocorticoid-induced-leucine-zipper protein (GILZ) in the whole kidney and in isolated cortical collecting tubules of adrenalectomized rats treated with low doses of aldosterone and/or dexamethasone. The resulting plasma concentrations of both steroids were close to 1 nmol/L. Aldosterone, given with or without dexamethasone, induced anti-natriuresis and kaliuresis, whereas dexamethasone alone did not. GILZ and ␣ENaC transcripts were higher after treatment with either or both hormones, whereas the mRNA abundance of Sgk-1 was increased in the cortical collecting tubule by aldosterone but not by dexamethasone. We conclude the increased expression of Sgk-1 in the cortical collecting tubules is a primary event in the early antinatriuretic and kaliuretic responses to physiologic concentrations of aldosterone. Induction of ␣ENaC and/or GILZ mRNAs may play a permissive role in the enhancement of the early and/or late responses; these effects may be necessary for a full response but do not by themselves promote early changes in urinary Na ϩ and K ϩ excretion.

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Section: Discussionsupporting

confidence: 90%

Mineralocorticoid Effects in the Kidney

Müller¹,

Парнова²,

Centeno³

et al. 2003

Journal of the American Society of Nephrology

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“…Sodium depletion did not increase sgk1, whereas it produced a robust induction of the three subunits of ENaC. Although previous studies (4,12,22,23) have shown ␣ENaC mRNA in the distal colon of animals fed a normal chow, there is no expression of protein or it is expressed at very low levels. Hence, the absence of electrogenic amiloride-sensitive sodium transport in the distal colon in basal conditions (12, 15) is likely due to expression of few channels and not to the presence of non- functional (i.e., silent) channels as is the case in the distal tubule of the kidney (14,20).…”

Section: Discussionmentioning

confidence: 62%

Expression of ENaC and serum- and glucocorticoid-induced kinase 1 in the rat intestinal epithelium

Ćorić

Hernandez

Rosa

et al. 2004

American Journal of Physiology-Gastrointestinal and Liver Physi

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. Expression of ENaC and serum-and glucocorticoid-induced kinase 1 in the rat intestinal epithelium. Am J Physiol Gastrointest Liver Physiol 286: G663-G670, 2004. First published November 20, 2003 10.1152/ ajpgi.00364.2003.-Increase in epithelium sodium channel (ENaC) activity induced by aldosterone in the distal tubule of the kidney has been attributed to serum-and glucocorticoid-induced kinase 1 (sgk1). The distal colon constitutes another classical aldosterone-responsive epithelium that expresses both ENaC and sgk1 in an aldosteronedependent manner. However, the site of expression and the temporal relationship of the aldosterone induction of these two proteins have not been investigated. Here, we examined the distribution and abundance of sgk1 in the rat intestine under basal conditions and after changes in the concentration of aldosterone and glucocorticoids. Results indicate that sgk1 is expressed in the distal colon and also in the ileum and jejunum. Abundance of sgk1 was high in control animals, and it did not change significantly after sodium depletion or after a single dose of aldosterone; however, it decreased after adrenalectomy. In contrast, the three subunits of ENaC were markedly induced in the distal colon by acute and chronic increases in aldosterone levels. Results indicate differential regulation of sgk and ENaC subunits by aldosterone in the distal colon. Distribution of sgk1 in the intestine beyond the aldosterone-responsive segments suggests that sgk1 may additionally regulate other sodium transporters in the intestinal epithelium. aldosterone; sodium depletion; distal colon; amiloride; serum-and glucocorticoid-induced kinase 1 DISTAL SEGMENTS OF THE renal tubule (21,24,28) and the epithelium of the distal colon (5, 32) respond to aldosterone by increasing amiloride-sensitive transepithelial sodium reabsorption. Epithelium sodium channel (ENaC), comprised of ␣-, ␤-and ␥-subunits, mediates the effects of aldosterone in both tissues, although the mechanisms underlying the response differ in the kidney and colon. Under basal conditions, neither the distal renal tubule nor the distal colon of the rat exhibits significant ENaC activity. However, the kidney expresses mRNA and protein of the three subunits; aldosterone increases transcription and translation of only the ␣-subunit by approximately twofold (4,20). The distal colon expresses ␣-mRNA and very low levels of ␤-and ␥-subunits; aldosterone increases the expression of mRNA of the three subunits, but the effect is 10-fold larger for ␤-and ␥-subunits than for ␣-subunits (4, 12, 18, 22).These observations imply that the early aldosterone response (29), which takes place within the first 2 h of administration of the hormone, differs in these tissues. In the cortical collecting tubule of the kidney, aldosterone may increase ENaC activity by translocation of channels to the apical membrane (19), by reducing the rate of endocytosis (10), or by activating previously silent channels (14). In the colon, however, aldosterone must first induce synthesi...

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“…This maneuver also augmented the effect of amiloride on renal Na ϩ excretion in these mice, tripled the amiloride-sensitive transepithelial short-circuit current in isolated perfused CCD to approximately 25% of the currents observed in glucocorticoid-treated wildtype mice, and restored plasma K ϩ . These data indicate that supraphysiologic glucocorticoid concentrations can activate glucocorticoid receptors in ASDN and thus, at least in part, compensate for a lack of MR (30). Together, these studies in…”

Section: Loss-of-function Mutants Of the Mineralocorticoid Receptormentioning

confidence: 53%

Lessons from Mouse Mutants of Epithelial Sodium Channel and Its Regulatory Proteins

Hummler¹,

Vallon²

2005

Journal of the American Society of Nephrology

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The use of gene-modified mouse models allows the experimental in vivo analysis of specific gene defects at the level of target cells. With respect to the epithelial sodium channel and some of its regulatory proteins, gene-modified models that control gene defects in a time-and tissue-dependent conditional or constitutive manner have been generated. The combination of molecular and physiologic approaches in these mouse models increases the understanding of the complex regulation and the cell signaling cascades involved in Na ؉ transport in target cells and may ultimately provide new insights into the pathophysiology of renal Na ؉ retention and BP regulation. This review summarizes and discusses the gene-targeting approaches that have been applied to the epithelial sodium channel and its regulatory proteins.

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Induction of the epithelial Na+ channel via glucocorticoids in mineralocorticoid receptor knockout mice

Cited by 45 publications

References 40 publications

Mineralocorticoid Effects in the Kidney

Mineralocorticoid Effects in the Kidney

Expression of ENaC and serum- and glucocorticoid-induced kinase 1 in the rat intestinal epithelium

Lessons from Mouse Mutants of Epithelial Sodium Channel and Its Regulatory Proteins

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