Rapid aldosterone actions on epithelial sodium channel trafficking and cell proliferation

Quinn, Sinéad; Harvey, Bill; Thomas, Warren

doi:10.1016/j.steroids.2013.11.005

Cited by 22 publications

(16 citation statements)

References 60 publications

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“…Likewise, recent studies using mice deficient for 11βHSD2 by Hunter and colleagues challenged the conventional concept of mineralocorticoid signaling in the DCT [10]. The possible contribution of non-genomic effects of aldosterone on NCC regulation is intriguing and awaits future studies [18].…”

Section: Discussionmentioning

confidence: 99%

The mineralocorticoid receptor (MR) regulates ENaC but not NCC in mice with random MR deletion

Czogalla

Vohra

Pentón

et al. 2016

Pflugers Arch - Eur J Physiol

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Aldosterone binds to the mineralocorticoid receptor (MR) and increases renal Na+ reabsorption via up-regulation of the epithelial Na+ channel (ENaC) and the Na+-K+-ATPase in the collecting system (CS) and possibly also via the NaCl cotransporter (NCC) in the distal convoluted tubule (DCT). However, whether aldosterone directly regulates NCC via MR, or indirectly through systemic alterations remains controversial. We used mice with deletion of MR in 20% of renal tubule cells (MR/X mice), in which MR-positive (MRwt) and -negative (MRko) cells can be studied sideby-side in the same physiological context. Adult MR/X mice showed similar mRNA and protein levels of renal ion transport proteins to control mice. In MR/X mice, no differences in NCC abundance and phosphorylation was seen between MRwt and MRko cells and dietary Na+ restriction up-regulated NCC to similar extent in both groups of cells. In contrast, MRko cells in the CS did not show any detectable alpha-ENaC abundance or apical targeting of ENaC neither on control diet nor in response to dietary Na+ restriction. Furthermore, Na+-K+-ATPase expression was unaffected in MRko cells of the DCT, while it was lost in MRko cells of the CS. In conclusion, MR is crucial for ENaC and Na+-K+-ATPase regulation in the CS, but is dispensable for NCC and Na+-K+-ATPase regulation in the DCT. PAEJ-D-16-00005 -NCC regulation is MR independent 2 ACKNOWLEDGEMENTSThe authors would like to thank Günter Schütz and Stefan Berger, Burkhard Becher, Celso E. Gomez-Sanchez, and Eric Feraille for kindly providing us with the MRlox/lox mouse line, the cmv-cre mouse line, the anti-MR antibodies, and the anti-Na + -K + -ATPase antibody, respectively. The expert technical assistance by Monique Carrel and Michèle Heidemeyer is gratefully acknowledged. GRANTS DISCLOSURESThe authors declare no conflict of interest, financial or otherwise. PAEJ-D-16-00005 -NCC regulation is MR independent 3 ABSTRACTAldosterone binds to the mineralocorticoid receptor (MR) and increases renal Na + reabsorption via up-regulation of the epithelial Na + channel (ENaC) and the Na + -K + -ATPase in the collecting system (CS) and possibly also via the NaCl cotransporter (NCC) in the distal convoluted tubule (DCT). However, whether aldosterone directly regulates NCC via MR, or indirectly through systemic alterations remains controversial. We used mice with deletion of MR in ~20% of renal tubule cells (MR/X mice), in which MR-positive (MR wt ) and -negative (MR ko ) cells can be studied sideby-side in the same physiological context. Adult MR/X mice showed similar mRNA and protein levels of renal ion transport proteins to control mice. In MR/X mice, no differences in NCC abundance and phosphorylation was seen between MR wt and MR ko cells and dietary Na + restriction up-regulated NCC to similar extent in both groups of cells. In contrast, MR ko cells in the CS did not show any detectable alphaENaC abundance or apical targeting of ENaC neither on control diet nor in response to dietary Na + restriction. Furtherm...

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Section: Discussionmentioning

confidence: 99%

The mineralocorticoid receptor (MR) regulates ENaC but not NCC in mice with random MR deletion

Czogalla

Vohra

Pentón

et al. 2016

Pflugers Arch - Eur J Physiol

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“…Expression of epithelial Na þ channel (ENaC) which is involved in Na þ and H 2 O reabsorption in the kidney was found to be up-regulated by aldosterone. 6 Under aldosterone influence, ENaC expression at the apical membrane of collecting ducts (CD) is markedly increased, associated with increased expression of the basolaterally located Na þ /K þ -ATPase. 7 Increase in Na þ reabsorption as a result of increased ENaC expression then drives secondary H 2 O reabsorption.…”

Section: Introductionmentioning

confidence: 99%

Effects of gonadectomy and testosterone treatment on aquaporin expression in the kidney of normotensive and hypertensive rats

Loh

Giribabu

Salleh

2017

Exp Biol Med (Maywood)

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We tested the hypothesis that testosterone-induced increase in blood pressure was due to changes in aquaporin (AQP) expression in kidneys. In this study, expression level of kidney AQPs was investigated under testosterone influence. Adult normotensive Wistar Kyoto (WKY) and hypertensive SHR male and female rats underwent gonadectomy. For female rats, testosterone was given for six weeks duration, two weeks following ovariectomy via subcutaneous silastic implant. Mean arterial pressure (MAP) was measured in all the rats after eight weeks via carotid artery cannulation and the rats were then sacrificed and kidneys were harvested for analyses of AQP-1, 2, 3, 4, 6, and 7 mRNA and protein expressions by quantitative real-time PCR and Western blotting, respectively. Distribution of AQP subunits' protein in kidneys was observed by immunofluorescence. In male WKY rats, MAP, AQP-1, 2, 4, and 7 protein; and mRNA expression decreased however AQP-3 protein and mRNA expression increased following orchidectomy. The vice versa effects were observed in testosterone-treated ovariectomized female WKY rats. However, no changes in AQP-6 expression were observed. Meanwhile, in adult male SHR rats, MAP and expression level of all AQP subunits decreased following orchidectomy. The opposite effects were seen in ovariectomized female SHR rats following testosterone treatment. Immunofluorescence study showed AQP-1 and AQP-7 were distributed in the proximal convoluted tubules (PCT) while AQP-2, AQP-4, and AQP-6 were distributed in the collecting ducts (CDs). AQP-3 was distributed in the PCT and CD. In conclusion, changes in AQP subunit expression in kidneys could explain changes in blood pressure under testosterone influence. Impact statement This study provides fundamental understanding on the mechanisms underlying testosterone-induced increase in blood pressure which involve regulation of aquaporin channel subunits in the kidneys. A better understanding of this issue can help to explain the reason for higher blood pressure in males as compared to females and may explain the reason for higher blood pressure in females after menopause than females before menopause, the former most probably related to the changes in female androgen.

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“…The tight regulation of transcellular Na + concentrations is so important that multiple mechanisms work in concert to control them. One of the main mechanisms controlling ENaC activity is activation of the RAAS (Pearce et al, 2014; Rossier, 2014; Quinn, Harvey, & Thomas, 2014; Alvarez et al, 2013). Activation of the RAAS is well known to enhance activity of ENaC.…”

Section: Regulation Of Sodium Reabsorption – Role Of Enacmentioning

confidence: 99%

Inhibition of ENaC by Endothelin-1

Sorokin

Staruschenko

2015

Hormones and Transport Systems

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The amiloride-sensitive epithelial Na+ channel (ENaC) is a key player in the regulation of Na+ homeostasis. Its functional activity is under continuous control by a variety of signaling molecules including bioactive peptides of endothelin family. Since ENaC dysfunction is causative for disturbances in total body Na+ levels associated with abnormal regulation of blood volume, blood pressure, and lung fluid balance, the uncovering the molecular mechanisms of inhibitory modulation or inappropriate activation of ENaC is crucial for the successful treatment of a variety of human diseases including hypertension. The precise regulation of ENaC is particularly important for normal Na+ and fluid homeostasis in organs where endothelins are known to act: kidneys, lung and colon. Inhibition of ENaC by endothelin-1 (ET-1) has been established in renal cells and several molecular mechanisms of inhibition of ENaC by ET-1 are proposed and will be reviewed in this chapter.

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Rapid aldosterone actions on epithelial sodium channel trafficking and cell proliferation

Cited by 22 publications

References 60 publications

The mineralocorticoid receptor (MR) regulates ENaC but not NCC in mice with random MR deletion

The mineralocorticoid receptor (MR) regulates ENaC but not NCC in mice with random MR deletion

Effects of gonadectomy and testosterone treatment on aquaporin expression in the kidney of normotensive and hypertensive rats

Inhibition of ENaC by Endothelin-1

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