Aldosterone-induced increase in the abundance of Na+ channel subunits

Asher, Carol; Wald, Hanna; Rossier, Bernard C.; Garty, Haim

doi:10.1152/ajpcell.1996.271.2.c605

Cited by 236 publications

(189 citation statements)

References 12 publications

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“…ENaC is a heterotrimer of α, β, and γ subunits, all of which are essential for channel functionality 30. The main target of MR in the kidneys is α‐ENaC, whereas in the intestine, β‐ and γ‐ENaC are the main targets 31, 32, 33. The reduction in β‐ and γ‐ENaC but not α‐ENaC expression in the colons of IEC‐MR‐KO mice was consistent with these previous findings.…”

Section: Discussionsupporting

confidence: 88%

Intestinal Mineralocorticoid Receptor Contributes to Epithelial Sodium Channel–Mediated Intestinal Sodium Absorption and Blood Pressure Regulation

Nakamura

Kurihara

Kobayashi

et al. 2018

JAHA

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BackgroundMineralocorticoid receptor (MR) has pathological roles in various cell types, including renal tubule cells, myocytes, and smooth muscle cells; however, the role of MR in intestinal epithelial cells (IECs) has not been sufficiently evaluated. The intestine is the sensing organ of ingested sodium; accordingly, intestinal MR is expected to have essential roles in blood pressure (BP) regulation.Methods and ResultsWe generated IEC‐specific MR knockout (IEC‐MR‐KO) mice. With a standard diet, fecal sodium excretion was 1.5‐fold higher in IEC‐MR‐KO mice, with markedly decreased colonic expression of β‐ and γ‐epithelial sodium channel, than in control mice. Urinary sodium excretion in IEC‐MR‐KO mice decreased by 30%, maintaining sodium balance; however, a low‐salt diet caused significant reductions in body weight and BP in IEC‐MR‐KO mice, and plasma aldosterone exhibited a compensatory increase. With a high‐salt diet, intestinal sodium absorption markedly increased to similar levels in both genotypes, without an elevation in BP. Deoxycorticosterone/salt treatment elevated BP and increased intestinal sodium absorption in both genotypes. Notably, the increase in BP was significantly smaller in IEC‐MR‐KO mice than in control mice. The addition of the MR antagonist spironolactone to deoxycorticosterone/salt treatment eliminated the differences in BP and intestinal sodium absorption between genotypes.ConclusionsIntestinal MR regulates intestinal sodium absorption in the colon and contributes to BP regulation. These regulatory effects are associated with variation in epithelial sodium channel expression. These findings suggest that intestinal MR is a new target for studying the molecular mechanism of hypertension and cardiovascular diseases.

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Section: Discussionsupporting

confidence: 88%

Intestinal Mineralocorticoid Receptor Contributes to Epithelial Sodium Channel–Mediated Intestinal Sodium Absorption and Blood Pressure Regulation

Nakamura

Kurihara

Kobayashi

et al. 2018

JAHA

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“…The actions of the PPARγ agonist pioglitazone on the distal nephron strongly resemble the actions of aldosterone, which also exerts both, SGK1-independent direct [3] and SGK1-dependent indirect effects on ENaC expression and activity [1,10,13,29,34]. As part of a counter-regulation to the pioglitazone-induced volume retention, endogenous aldosterone levels were suppressed.…”

Section: Discussionmentioning

confidence: 96%

Lack of the serum and glucocorticoid-inducible kinase SGK1 attenuates the volume retention after treatment with the PPARγ agonist pioglitazone

Artunc

Sandulache

Nasir

et al. 2008

Pflugers Arch - Eur J Physiol

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PPARγ-agonists enhance insulin sensitivity and improve glucose utilization in diabetic patients. Adverse effects of PPARγ-agonists include volume retention and edema formation. Recent observations pointed to the ability of PPARγ agonists to enhance transcription of the serum and glucocorticoid-inducible kinase SGK1, a kinase that is genomically upregulated by mineralocorticoids and stimulates various renal channels and transporters including the renal epithelial Na + channel ENaC. SGK1 has been proposed to mediate the volume retention after treatment with PPARγ agonists. To test this hypothesis, food containing the PPARγ agonist pioglitazone (0.02%, i.e., approximately 25 mg/kg bw/day) was administered to gene-targeted mice lacking SGK1 (sgk1 −/− , n=12) and their wild-type littermates (sgk1 +/+ , n=12). According to in situ hybridization, quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and immunofluorescence, treatment with pioglitazone significantly increased renal SGK1 mRNA and protein expression in sgk1 +/+ mice. The treatment increased body weight significantly in both, sgk1 +/+ mice (+2.2±0.3 g) and sgk −/− mice (+1.3±0.2 g), and decreased hematocrit significantly in sgk1 +/+ mice (−6.5±1.0%) and sgk1 −/− mice (−3.1±0.6%). Both effects were significantly (p<0.05) more pronounced in sgk1 +/+ mice. According to Evans Blue

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“…Previous work has examined kidney expression of ENaC in the rat (Renard et al 1995, Asher et al 1996, Escoubet et al 1997, Stokes & Sigmund 1998, with modest upregulation of ENaC being reported. However, mineralocorticoid doses used in those rat studies were largely in the pharmacological range (5-to 15-fold greater) (Renard et al 1995, Asher et al 1996, Stokes & Sigmund 1998. In the present study, an upregulation of the level of ENaC mRNA of equal degree was seen across physiological changes in circulating aldosterone.…”

Section: Discussionmentioning

confidence: 99%

Corticosteroid regulation of amiloride-sensitive sodium-channel subunit mRNA expression in mouse kidney

MacDonald¹,

MacKenzie²,

Ramage³

et al. 2000

Journal of Endocrinology

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Corticosteroid control of distal nephron sodium handling, particularly through the amiloride-sensitive sodium channel (ENaC), has a key role in blood pressure regulation. The mechanisms regulating ENaC activity remain unclear. Despite the generation of useful mouse models of disorders of electrolyte balance and blood pressure, there has been little study of distal nephron sodium handling in this species. To investigate how corticosteroids regulate ENaC activity we isolated cDNA for the three mouse ENaC subunits ( , and ), enabling their quantitation by competitive PCR and in situ hybridisation. Kidneys were analysed from mice 6 days after adrenalectomy or placement of osmotic mini-pumps delivering aldosterone (50 µg/kg per day), dexamethasone (100 µg/kg per day), spironolactone (20 mg/kg per day) or vehicle alone (controls). In controls, renal ENaC mRNA exceeded or by approximately 1·75-to 2·8-fold. All subunit mRNAs were expressed in renal cortex and outer medulla, where the pattern of expression was fully consistent with localisation in collecting duct, whereas the distribution in cortex suggested expression extended beyond the collecting duct into adjacent distal tubule. Subunit mRNA expression decreased from cortex to outer medulla, with a gradual reduction in and , and ENaC decreased sharply (50%) across the outer medulla. Expression of ENaC and (but not ) extended into inner medulla, suggesting the potential for inner medulla collecting duct cation channels in which at least ENaC participate. Aldosterone significantly increased ENaC subunit expression; the other treatments had little effect. Aldosterone caused a 1·9-to 3·5-fold increase in ENaC (particularly marked in outer medullary collecting duct), but changes for and were minor and limited to the cortex. The results raise the possibility that medullary ENaC upregulation by aldosterone will create more favourable subunit stoichiometry leading to a more substantial increase in ENaC activity. In cortex, such a mechanism is unlikely to have a major role.

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Aldosterone-induced increase in the abundance of Na+ channel subunits

Cited by 236 publications

References 12 publications

Intestinal Mineralocorticoid Receptor Contributes to Epithelial Sodium Channel–Mediated Intestinal Sodium Absorption and Blood Pressure Regulation

Intestinal Mineralocorticoid Receptor Contributes to Epithelial Sodium Channel–Mediated Intestinal Sodium Absorption and Blood Pressure Regulation

Lack of the serum and glucocorticoid-inducible kinase SGK1 attenuates the volume retention after treatment with the PPARγ agonist pioglitazone

Corticosteroid regulation of amiloride-sensitive sodium-channel subunit mRNA expression in mouse kidney

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