Mechanisms of Aldosterone's Action on Epithelial Na + Transport

Eaton, Douglas C.; Malik, Bela; Saxena, N.C.; Al‐Khalili, Otor; Yue, Gang

doi:10.1007/s00232-001-0098-x

Cited by 83 publications

(57 citation statements)

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“…Others conclude that the effect is due exclusively to an increase in channel density (27), and that aldosterone, vasopressin, and insulin act on sodium transport by promoting the incorporation of channels in the apical membrane (28). Conversely, several groups have suggested that aldosterone increases the ENaC open probability (15), possibly by posttranslational modification (26,29). It has been suggested that regulation of trafficking and͞or functioning of sodium channels is controlled by aldosterone-induced modulatory proteins and kinases (30).…”

Section: Resultsmentioning

confidence: 99%

“…It has been suggested that regulation of trafficking and͞or functioning of sodium channels is controlled by aldosterone-induced modulatory proteins and kinases (30). One regulatory cascade proposed acts via aldosterone-induced expression of small G protein K-Ras2A, with subsequent activation of PI3K, which produces phosphoinositol-3,4,5-trisphosphate (PIP 3 ) and that this is a direct regulator of ENaC open probability (29). This regulation also involves serum-and glucocorticoid-kinase (SGK1) that prevents ENaC degradation and mitogen-activated protein kinase (MAPK) that in contrast stimulates channel degradation (31,32).…”

Section: Resultsmentioning

confidence: 99%

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Aldosterone acts via an ATP autocrine/paracrine system: The Edelman ATP hypothesis revisited

Gorelik

Zhang

Sánchez

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Aldosterone, the most important sodium-retaining hormone, was first characterized >50 years ago. However, despite numerous studies including the classical work of Isidore S. ''Izzy'' Edelman showing that aldosterone action depended on ATP production, the mechanism by which it activates sodium reabsorption via the epithelial sodium channel remains unclear. Here, we report experiments that suggest that one of the key steps in aldosterone action is via an autocrine͞paracrine system. The hormone stimulates ATP release from the basolateral side of the target kidney cell. Prevention of ATP accumulation or its removal blocks aldosterone action. ATP then acts via a purinergic mechanism to produce contraction of small groups of adjacent epithelial cells. Patch clamping demonstrates that it is these contracted cells that have channel activity. With progressive recruitment of contracting cells, there is then a parallel increase in transepithelial electrical conductance. In common with other stimuli of sodium transport, this pathway involves phosphatidylinositol 3-kinase. Inhibition of phosphatidylinositol 3-kinase blocks both cell contraction and conductance. We put forward the hypothesis that redistribution of the cell volume caused by the lateral contraction results in apical swelling and that this change, in turn, disrupts the epithelial sodium channel interaction with the F-actin cytoskeleton, opening the channel and hence increasing sodium transport.scanning ion conductance microscopy ͉ scanning probe microscopy ͉ epithelial sodium channel ͉ renal epithelium T he sodium homeostasis regulatory hormone aldosterone was first identified in 1953 (1). Early studies on the biochemical mechanism of its action were reviewed by Edelman and Fimognari (2). This work was greatly helped by the introduction by Ussing and Zerahn (3) of the short-circuit current method for measuring sodium transport. Jean Crabbé (4, 5) first demonstrated the effect of aldosterone on sodium transport across toad bladder and skin and drew attention to the latent period of 60-90 min in the action of aldosterone. He postulated the synthesis or activation of an intermediate by aldosterone. Work by Edelman et al. (6) showed that inhibition of DNA-dependent RNA synthesis and of protein synthesis blocked the aldosterone effect. Edelman et al. (6) went on to demonstrate that aldosterone activation of sodium transport was critically dependent on ATP production. In substrate-depleted toad bladders, aldosterone had little or no effect, but the response was restored by adding glucose or pyruvate to the medium. Edelman suggested that a possible explanation of this absolute dependence on substrate was that, in the energy-depleted system, the rate of activation of sodium transport was limited by the local concentration of ATP. However, he felt that this hypothesis was questionable given that substrate-depleted toad bladders responded to vasopressin and to amphotericin B with a normal increase in sodium transport. This work became known as the ATP generation hypothe...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Aldosterone acts via an ATP autocrine/paracrine system: The Edelman ATP hypothesis revisited

Gorelik

Zhang

Sánchez

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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“…Sodium reabsorption in the aldosterone-sensitive distal nephron (ASDN), 3 which includes the connecting tubule and the cortical collecting duct (CCD), determines final concentration of Na ϩ excreted in urine (3)(4)(5). Activity of the epithelial Na ϩ channel (ENaC) accounts for electrogenic Na ϩ reabsorption at this segment (3,4,6,7). Therefore, ENaC is critical for regulation of sodium balance and circulating volume (4,(7)(8)(9)(10).…”

Section: Whereas Regulation Of Enac By Aldosterone Is Generally Accepmentioning

confidence: 99%

“…ENaC-mediated Na ϩ reabsorption also provides the electrical driving force for K ϩ secretion mediated by the renal outer medullary K ϩ (ROMK) channel and the "big conductance" K ϩ channel (15). ENaC activity in the ASDN is regulated by the renin-angiotensin-aldosterone system (RAAS) in response to variations in dietary Na ϩ intake with aldosterone being the primary ENaC activator (4,6,7). Elevations in circulating aldosterone levels increase ␣-ENaC expression and redistribution of ␤-and ␥-ENaC from cytosol to the apical membrane (16,17).…”

Section: Whereas Regulation Of Enac By Aldosterone Is Generally Accepmentioning

confidence: 99%

Angiotensin II Increases Activity of the Epithelial Na+ Channel (ENaC) in Distal Nephron Additively to Aldosterone

Mamenko

Zaika

Ilatovskaya

et al. 2012

Journal of Biological Chemistry

132

123

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“…Aldosterone is a major regulator of epithelial Na ϩ absorption and acts in large part through ENaC induction in the renal collecting duct (3,4). Aldosterone administration or hyperaldosteronism induced by a low-Na ϩ diet increases ENaC␣ gene transcription, without increasing ␤-or ␥-subunit expression (5-9), and without a separate effect on ENaC␣ mRNA turnover (10) in this segment.…”

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confidence: 99%

Dot1a-AF9 Complex Mediates Histone H3 Lys-79 Hypermethylation and Repression of ENaCα in an Aldosterone-sensitive Manner

Zhang¹,

Xia²,

Reisenauer³

et al. 2006

Journal of Biological Chemistry

153

231

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Aldosterone is a major regulator of epithelial Na؉ absorption and acts in large part through induction of the epithelial Na ؉ channel (ENaC) gene in the renal collecting duct. We previously identified Dot1a as an aldosterone early repressed gene and a repressor of ENaC␣ transcription through mediating histone H3 Lys-79 methylation associated with the ENaC␣ promoter. Here, we report a novel aldosterone-signaling network involving AF9, Dot1a, and ENaC␣. AF9 and Dot1a interact in vitro and in vivo as evidenced in multiple assays and colocalize in the nuclei of mIMCD3 renal collecting duct cells. Overexpression of AF9 results in hypermethylation of histone H3 Lys-79 at the endogenous ENaC␣ promoter at most, but not all subregions examined, repression of endogenous ENaC␣ mRNA expression and acts synergistically with Dot1a to inhibit ENaC␣ promoter-luciferase constructs. In contrast, RNA interference-mediated knockdown of AF9 causes the opposite effects. Chromatin immunoprecipitation assays reveal that overexpressed FLAG-AF9, endogenous AF9, and Dot1a are each associated with the ENaC␣ promoter. Aldosterone negatively regulates AF9 expression at both mRNA and protein levels. Thus, Dot1a-AF9 modulates histone H3 Lys-79 methylation at the ENaC␣ promoter and represses ENaC␣ transcription in an aldosterone-sensitive manner. This mechanism appears to be more broadly applicable to other aldosterone-regulated genes because overexpression of AF9 alone or in combination with Dot1a inhibited mRNA levels of three other known aldosterone-inducible genes in mIMCD3 cells.The epithelial sodium channel (ENaC) 2 is a heteromultimeric protein composed of three partially homologous subunits (␣, ␤, and ␥) that is expressed in the apical membrane of salt-absorbing epithelia of kidney, colon, and lung where it constitutes the rate-limiting steps in active Na ϩ and fluid absorption. ENaC plays a major role in the regulation of salt homeostasis and blood pressure as evidenced by the fact that ENaC mutations are associated with genetic hypertensive and hypotensive diseases, such as Liddle's syndrome (1) and pseudohypoaldosteronism type 1 (2), and the fact that it is subject to tight and complex regulation by aldosterone. Aldosterone is a major regulator of epithelial Na ϩ absorption and acts in large part through ENaC induction in the renal collecting duct (3, 4). Aldosterone administration or hyperaldosteronism induced by a low-Na ϩ diet increases ENaC␣ gene transcription, without increasing ␤-or ␥-subunit expression (5-9), and without a separate effect on ENaC␣ mRNA turnover (10) in this segment. Although ENaC␣ synthesis is believed to be the rate-limiting step in Na ϩ channel formation in the collecting duct, only limited information exists regarding the specific mechanisms governing transcriptional regulation of this gene, in particular epigenetic mechanisms exerting such controls.Traditional models of aldosterone trans-activation of target genes, including ENaC␣, have emphasized interaction of the liganded mineralocorticoid receptor or g...

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Mechanisms of Aldosterone's Action on Epithelial Na + Transport

Cited by 83 publications

References 0 publications

Aldosterone acts via an ATP autocrine/paracrine system: The Edelman ATP hypothesis revisited

Aldosterone acts via an ATP autocrine/paracrine system: The Edelman ATP hypothesis revisited

Angiotensin II Increases Activity of the Epithelial Na+ Channel (ENaC) in Distal Nephron Additively to Aldosterone

Dot1a-AF9 Complex Mediates Histone H3 Lys-79 Hypermethylation and Repression of ENaCα in an Aldosterone-sensitive Manner

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