Differential subcellular localization of ENaC subunits in mouse kidney in response to high- and low-Na diets

Loffing, Johannes; Piétri, Laurence; Aregger, Fintan; Bloch-Faure, May; Ziegler, Urs; Meneton, Pierre; Rossier, Bernard C.; Kaissling, Brigitte

doi:10.1152/ajprenal.2000.279.2.f252

Cited by 208 publications

(227 citation statements)

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“…30 Under NaCl-replete conditions, ␣ENaC is present in collecting duct cells at very low levels, whereas ␤ and ␥ENaC appear to be sequestered intracellularly. 19,25 With dietary NaCl restriction, ␣ENaC is strongly induced in the kidney and all 3 subunits are readily detectable in the apical region of the cells, presumably in the apical plasma membrane. 19,25 Aldosterone has been seen to strongly upregulate the abundance of ␣ENaC in kidney, both at the protein 19 and mRNA 26 levels and, until now, has been believed to be the main factor responsible of the induction of ␣ENaC in the setting of dietary NaCl restriction.…”

Section: Discussionmentioning

confidence: 99%

“…19,25 With dietary NaCl restriction, ␣ENaC is strongly induced in the kidney and all 3 subunits are readily detectable in the apical region of the cells, presumably in the apical plasma membrane. 19,25 Aldosterone has been seen to strongly upregulate the abundance of ␣ENaC in kidney, both at the protein 19 and mRNA 26 levels and, until now, has been believed to be the main factor responsible of the induction of ␣ENaC in the setting of dietary NaCl restriction. In the present study, AT 1 receptor blockade with candesartan in NaCl-restricted rats had a consistent effect of decreasing the abundance of ␣ENaC (demonstrated in multiple experiments), and this effect was not blocked by spironolactone at a dose that has been found to be sufficient to fully block the mineralocorticoid receptor.…”

Section: Discussionmentioning

confidence: 99%

“…Without candesartan infusion, both subunits were restricted to the apical regions of the collecting duct principal cells as previously seen after dietary NaCl restriction. 19,25 In contrast, after candesartan infusion, both subunit proteins were distributed throughout the cells.…”

Section: Effect Of Candesartan On Cellular Localization Of Enacmentioning

confidence: 95%

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Long-Term Regulation of ENaC Expression in Kidney by Angiotensin II

et al. 2003

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Abstract-We carried out semiquantitative immunoblotting of kidney to identify apical sodium transporter proteins whose abundances are regulated by angiotensin II. In NaCl-restricted rats (0.5 mEq Na/200 g BW/d), the type 1 angiotensin II receptor (AT 1 receptor) antagonist, candesartan, (1 mg/kg of body weight per day SC for 2 days) markedly decreased the abundance of the ␣ subunit of the epithelial sodium channel (ENaC). This subunit has been shown to be rate-limiting for assembly of mature ENaC complexes. In addition, systemic infusion of angiotensin II increased ␣ENaC protein abundance in rat kidney cortex. The decrease in ␣ENaC protein abundance in response to AT 1 receptor blockade was associated with a fall in ␣ENaC mRNA abundance (real-time RT-PCR), consistent with transcriptionally mediated regulation. The effect of AT 1 receptor blockade on ␣ENaC expression was not blocked by spironolactone, suggesting a direct role of the AT 1 receptor in regulation of ␣ENaC gene expression. Candesartan administration was also found to increase the abundances of the ␤ and ␥ subunits. The increase in ␤ and ␥ENaC protein abundance was not associated with a significant increase in the renal abundances of the corresponding mRNAs, suggesting a posttranscriptional mechanism. Immunocytochemistry confirmed the increase in ␤ and ␥ENaC protein abundance and demonstrated candesartan-induced ENaC internalization in collecting duct cells. The results support the view that the angiotensin II receptor regulates ENaC abundance, consistent with a role for angiotensin II in regulation of collecting duct function. Key Words: receptors, angiotensin II Ⅲ angiotensin antagonist Ⅲ sodium channels Ⅲ aldosterone L ong-term control of blood pressure is closely tied to sodium balance and extracellular fluid volume regulation, both of which are controlled in part by the renin-angiotensin-aldosterone system (RAAS). 1 Angiotensin II has important nonrenal effects that are instrumental in the control of blood pressure as both a vasoconstrictor and a regulator of aldosterone secretion. In addition, angiotensin II has direct effects on the renal tubule in regulating NaCl reabsorption. 2 The direct antinatriuretic effects of angiotensin II appear to be particularly important in conditions of dietary sodium restriction or contraction of extracellular fluid volume. 1 Regulation of renal tubule sodium transport by angiotensin II has been investigated chiefly in relatively short-term experiments with observations within a few minutes of angiotensin II addition. 3-7 However, there is growing evidence that a variety of mediators of transport regulation in the kidney, such as vasopressin 8 and aldosterone, 9 work by both short-term and long-term actions. The long-term actions are associated with adaptive increases in abundance of transporter proteins, whereas short-term actions are generally associated with regulated trafficking or posttranslational modifications of the transporter proteins.The antinatriuretic effects of angiotensin II on sodium transport are...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Long-Term Regulation of ENaC Expression in Kidney by Angiotensin II

et al. 2003

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“…26 The apical ENaC expression has also been shown to be more pronounced in the CNT compared with the CD in mice on a moderately low-sodium diet (0.05%). 27 That a partial gene deletion in the CNT was sufficient to induce a severe salt-losing syndrome also shows that the functional reserve in the CNT is limited because the remaining ␣ENaC-positive CNT cells were unable to compensate fully for the loss of ␣ENaC in the other cells.…”

Section: The Cnt Is Critical For the Enac-mediated Sodium Reabsorptionmentioning

confidence: 99%

Sodium and Potassium Balance Depends on αENaC Expression in Connecting Tubule

Christensen¹,

Perrier²,

Wang

et al. 2010

Journal of the American Society of Nephrology

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Mutations in ␣, ␤, or ␥ subunits of the epithelial sodium channel (ENaC) can downregulate ENaC activity and cause a severe salt-losing syndrome with hyperkalemia and metabolic acidosis, designated pseudohypoaldosteronism type 1 in humans. In contrast, mice with selective inactivation of ␣ENaC in the collecting duct (CD) maintain sodium and potassium balance, suggesting that the late distal convoluted tubule (DCT2) and/or the connecting tubule (CNT) participates in sodium homeostasis. To investigate the relative importance of ENaC-mediated sodium absorption in the CNT, we used Cre-lox technology to generate mice lacking ␣ENaC in the aquaporin 2-expressing CNT and CD. Western blot analysis of microdissected cortical CD (CCD) and CNT revealed absence of ␣ENaC in the CCD and weak ␣ENaC expression in the CNT. These mice exhibited a significantly higher urinary sodium excretion, a lower urine osmolality, and an increased urine volume compared with control mice. Furthermore, serum sodium was lower and potassium levels were higher in the genetically modified mice. With dietary sodium restriction, these mice experienced significant weight loss, increased urinary sodium excretion, and hyperkalemia. Plasma aldosterone levels were significantly elevated under both standard and sodium-restricted diets. In summary, ␣ENaC expression within the CNT/CD is crucial for sodium and potassium homeostasis and causes signs and symptoms of pseudohypoaldosteronism type 1 if missing.

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“…Its Na ϩ -saving action is mediated ␥ENaC Determines Na ϩ Absorption by the activity of ENaC in the apical membrane aldosterone-responsive tissues such as the kidney and distal colon. A differential expression of different ENaC subunits in response to aldosterone has been observed in different tissues with a marked increase in ␣ENaC mRNA in mouse and rat kidney [21][22][23], but enhanced ␤ and ␥ENaC mRNA expressions in rat distal colon [24][25][26]. These differences could be due to tissue-specific transcription efficiency, and no firm conclusion can be drawn as to which specific subunit is responsible for aldosterone-enhanced ENaC activity since no direct demonstration has been made linking transcriptional changes directly to functional variations in ENaC activity.…”

Section: Introductionmentioning

confidence: 99%