A low-Na + diet enhances expression of mRNA for epithelial Na + channel in rat renal inner medulla

Ono, S.; Kusano, Eiji; Muto, Shigeaki; Ando, Yumiko; Asano, Yoshihide

doi:10.1007/s004240050462

Cited by 37 publications

(29 citation statements)

References 16 publications

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“…Quantitative real-time RT-PCR of total RNAs isolated from these same kidneys revealed that ENaCα and Sgk1 mRNA levels were similar to those of controls (normal salt) in the mice fed the high-salt diet, but 3- to 4-fold greater than controls in mice fed the low-salt diet ( Figure 6B). These findings are consistent with previous studies showing that a low-salt diet induces ENaCα mRNA expression in renal cortex and outer and inner medulla (14) as well as Sgk1 mRNA levels in renal cortex (15).…”

Section: Mutation Of the Sgk1 Phosphorylation Site Ser435 In Af9 Impasupporting

confidence: 93%

Aldosterone-induced Sgk1 relieves Dot1a-Af9–mediated transcriptional repression of epithelial Na+ channel α

Zhang¹,

Xia²,

et al. 2007

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Aldosterone plays a major role in the regulation of salt balance and the pathophysiology of cardiovascular and renal diseases. Many aldosterone-regulated genes -including that encoding the epithelial Na + channel (ENaC), a key arbiter of Na + transport in the kidney and other epithelia -have been identified, but the mechanisms by which the hormone modifies chromatin structure and thus transcription remain unknown. We previously described the basal repression of ENaCα by a complex containing the histone H3 Lys79 methyltransferase disruptor of telomeric silencing alternative splice variant a (Dot1a) and the putative transcription factor ALL1-fused gene from chromosome 9 (Af9) as well as the release of this repression by aldosterone treatment. Here we provide evidence from renal collecting duct cells and serum-and glucocorticoid-induced kinase-1 (Sgk1) WT and knockout mice that Sgk1 phosphorylated Af9, thereby impairing the Dot1a-Af9 interaction and leading to targeted histone H3 Lys79 hypomethylation at the ENaCα promoter and derepression of ENaCα transcription. Thus, Af9 is a physiologic target of Sgk1, and Sgk1 negatively regulates the Dot1a-Af9 repressor complex that controls transcription of ENaCα and likely other aldosterone-induced genes. IntroductionThe renin-angiotensin-aldosterone system plays a major role in the control of blood pressure, extracellular fluid volume, and electrolyte balance, largely through the regulation of urinary Na + excretion. The aldosterone-sensitive distal nephron (ASDN), composed of the late distal convoluted tubule, connecting tubule, and cortical and medullary collecting ducts, is the final arbiter of renal Na + excretion. In the ASDN, transepithelial Na + absorption occurs by apical Na + entry via the epithelial Na + channel (ENaC) and basolateral Na + exit via the Na + ,K + -ATPase. ENaC, composed of 3 subunits (α, β, and γ), constitutes the rate-limiting step in this process, and changes in its activity and/or plasma membrane abundance constitute key regulatory steps. Aldosterone increases transepithelial Na + transport in the ASDN in large part through ENaCα induction in this region (1). Aldosterone increases ENaC function in 2 phases: an early phase involving upregulation of preexisting transport machinery and aldosterone-induced regulatory proteins, notably serum- and glucocorticoid-induced kinase-1 (Sgk1), which regulates the plasma membrane abundance of ENaC in part through phosphorylation of the ubiquitin ligase Nedd4-2 (2); and a delayed phase of aldosterone action involving de novo synthesis of ENaC, either from the liganded mineralocorticoid receptor directly binding hormone response elements in the ENaCα promoter to activate transcription (1) or through indirect

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Section: Mutation Of the Sgk1 Phosphorylation Site Ser435 In Af9 Impasupporting

confidence: 93%

Aldosterone-induced Sgk1 relieves Dot1a-Af9–mediated transcriptional repression of epithelial Na+ channel α

Zhang¹,

Xia²,

et al. 2007

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“…Renard et al (5) demonstrated no changes in renal mRNA levels for any of the 3 subunits in response to dietary sodium restriction. However, other investigators (11)(12)(13)(14) found moderate increases in renal αENaC mRNA levels in response to increased circulating aldosterone concentrations, at least in some portions of the kidney. The present studies establish, both by immunoblotting and immunocytochemistry, that αENaC protein abundance in collecting duct principal cells is very low under control conditions and undergoes a multifold increase in response to aldosterone.…”

Section: Discussionmentioning

confidence: 92%

Aldosterone-mediated regulation of ENaC α, β, and γ subunit proteins in rat kidney

Masilamani¹,

Kim²,

Mitchell³

et al. 1999

J. Clin. Invest.

681

799

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“…Therefore, we speculate that the increase in ␣-ENaC protein abundance in the cortex was mediated, at least in part, by posttranscriptional mechanisms, e.g., regulation of ␣-ENaC mRNA translation (24). Different conclusions have been drawn for the renal medulla, in which dietary NaCl restriction has been found to consistently increase ␣-ENaC mRNA abundance (29,34).…”

Section: Relationship Between Mrna and Protein Levelsmentioning

confidence: 97%

Time course of renal Na-K-ATPase, NHE3, NKCC2, NCC, and ENaC abundance changes with dietary NaCl restriction

Masilamani

Wang

Kim

et al. 2002

American Journal of Physiology-Renal Physiology

113

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We have used peptide-directed antibodies to each major renal Na transporter and channel proteins to screen renal homogenates for changes in Na transporter protein expression after initiation of dietary NaCl restriction. After equilibration on a NaCl-replete diet (2.0 meq · 200 g body wt−1 · day−1), rats were switched to a NaCl-deficient diet (0.02 meq · 200 g body wt−1 · day−1). Na excretion fell to 25% of baseline levels on day 1, followed by a further decrease <4% of baseline levels on day 3, of NaCl restriction. The decreased Na excretion at day 1 occurred despite the absence of a significant increase in plasma aldosterone level or in the abundance of any of the major renal Na transporters. However, after a 1-day lag, plasma aldosterone levels increased in association with increases in abundances of three aldosterone-regulated Na transporter proteins: the thiazide-sensitive Na-Cl cotransporter (NCC), the α-subunit of the amiloride-sensitive epithelial Na channel (α-ENaC), and the 70-kDa form of γ-ENaC. RNase protection assays of transporter mRNA levels revealed an increase in renal α-ENaC mRNA coincident with the increase in α-ENaC protein abundance. However, there was no change in NCC mRNA abundance, suggesting that the increase in NCC protein in response to dietary NaCl restriction was not a result of altered gene transcription. These results point to early regulatory processes that decrease renal Na excretion without an increase in the abundance of any Na transporter, followed by a late aldosterone-dependent response associated with upregulation of NCC and ENaC.

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A low-Na + diet enhances expression of mRNA for epithelial Na + channel in rat renal inner medulla

Cited by 37 publications

References 16 publications

Aldosterone-induced Sgk1 relieves Dot1a-Af9–mediated transcriptional repression of epithelial Na+ channel α

Aldosterone-induced Sgk1 relieves Dot1a-Af9–mediated transcriptional repression of epithelial Na+ channel α

Aldosterone-mediated regulation of ENaC α, β, and γ subunit proteins in rat kidney

Time course of renal Na-K-ATPase, NHE3, NKCC2, NCC, and ENaC abundance changes with dietary NaCl restriction

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