scholarly journals Regulation of the epithelial sodium channel by accessory proteins

2003 ◽  
Vol 371 (1) ◽  
pp. 1-14 ◽  
Author(s):  
Kelly GORMLEY ◽  
Yanbin DONG ◽  
Giuseppe A. SAGNELLA
Keyword(s):  
Blood Pressure ◽  
Cystic Fibrosis ◽  
Sodium Channel ◽  
Sodium Transport ◽  
Genetic Disorders ◽  
Epithelial Sodium Channel ◽  
Sodium Balance ◽  
Sodium Reabsorption ◽  
Channel Activity ◽  
Cellular Mechanisms

The epithelial sodium channel (ENaC) is of fundamental importance in the control of sodium fluxes in epithelial cells. Modulation of sodium reabsorption through the distal nephron ENaC is an important component in the overall control of sodium balance, blood volume and thereby of blood pressure. This is clearly demonstrated by rare genetic disorders of sodium-channel activity (Liddle's syndrome and pseudohypoaldosteronism type 1), associated with contrasting effects on blood pressure. The mineralocorticoid aldosterone is a well-established modulator of sodium-channel activity. Considerable insight has now been gained into the intracellular signalling pathways linking aldosterone-mediated changes in gene transcription with changes in ion transport. Activating pathways include aldosterone-induced proteins and especially the serum- and glucocorticoid-inducible kinase (SGK) and the small G-protein, K-Ras 2A. Targeting of the ENaC for endocytosis and degradation is now emerging as a major mechanism for the down-regulation of channel activity. Several proteins acting in concert are an intrinsic part of this process but Nedd4 (neural precursor cell expressed developmentally down-regulated 4) is of central importance. Other mechanisms known to interact with ENaC and affect sodium transport include channel-activating protease 1 (CAP-1), a membrane-anchored protein, and the cystic fibrosis transmembrane regulator. The implications of research on accessory factors controlling ENaC activity are wide-ranging. Understanding cellular mechanisms controlling ENaC activity may provide a more detailed insight not only of ion-channel abnormalities in cystic fibrosis but also of the link between abnormal renal sodium transport and essential hypertension.

Abstract 076: Urinary Exosomal Epithelial Sodium Channel And Sodium-chloride Cotransporter Measurement In Humans

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
TAOPHEEQ A MUSTAPHA ◽  
VICTOR NWAZUE ◽  
KEVIN SCHEY ◽  
RAJ SATISH ◽  
JAMES M LUTHER
Keyword(s):  
Sodium Chloride ◽  
Sodium Channel ◽  
Multiple Reaction Monitoring ◽  
Epithelial Sodium Channel ◽  
Sodium Balance ◽  
Sodium Reabsorption ◽  
Dependent Manner ◽  
Creatinine Concentration ◽  
Spot Urine ◽  
Sodium Chloride Cotransporter

Sodium reabsorption in the distal nephron is tightly regulated in part by epithelial sodium channel (ENaC) and sodium chloride cotransporter (NCC), although non-invasive measure of these proteins in humans has not previously been feasible. We recently analyzed the urinary exosomal proteome and identified candidate targets for quantification of ENaC and NCC using targeted mass spectrometry. To test the hypothesis that urinary exosomal ENaC and NCC are altered during renin-angiotensin-aldosterone system activation, we activated the endogenous RAAS using a low sodium diet (LS) in two separate studies. We provided 8 subjects LS diet (10mmol/day for 7days) to assess urinary protein excretion at 7 days (study 1) and longitudinally over the course of 1 week (study 2). Daily 24-hour urine was collected to monitor sodium balance, and spot urine samples were obtained each morning on days 0, 2, 4, and 6 of LS diet. Urinary exosomal ENaC-α, ENaC-γ, and NCC peptides were analyzed using targeted multiple-reaction-monitoring analysis quantified with stable-isotope peptide standards, and results were normalized to urine creatinine concentration. In study 1, urinary ENaCγ increased after 8 days of LS diet (Figure A). In study 2, urinary exosomal ENaCγ (Figure B) and NCC peptides (Figure C) increased in a time-dependent manner during LS diet. These measures of urinary sodium channel expression may provide further insight into distal sodium reabsorption in human hypertension.

Vasopressin-mediated regulation of epithelial sodium channel abundance in rat kidney

2000 ◽  
Vol 279 (1) ◽  
pp. F46-F53 ◽  
Author(s):  
Carolyn A. Ecelbarger ◽  
Gheun-Ho Kim ◽  
James Terris ◽  
Shyama Masilamani ◽  
Carter Mitchell ◽  
...  
Keyword(s):  
Sodium Channel ◽  
Sodium Transport ◽  
Collecting Duct ◽  
Rat Kidney ◽  
Epithelial Sodium Channel ◽  
Sodium Reabsorption ◽  
Acute Administration ◽  
Brattleboro Rats ◽  
Water Restriction ◽  
Short Term

Sodium transport is increased by vasopressin in the cortical collecting ducts of rats and rabbits. Here we investigate, by quantitative immunoblotting, the effects of vasopressin on abundances of the epithelial sodium channel (ENaC) subunits (α, β, and γ) in rat kidney. Seven-day infusion of 1-deamino-[8-d-arginine]-vasopressin (dDAVP) to Brattleboro rats markedly increased whole kidney abundances of β- and γ-ENaC (to 238% and 288% of vehicle, respectively), whereas α-ENaC was more modestly, yet significantly, increased (to 142% of vehicle). Similarly, 7-day water restriction in Sprague-Dawley rats resulted in significantly increased abundances of β- and γ- but no significant change in α-ENaC. Acute administration of dDAVP (2 nmol) to Brattleboro rats resulted in modest, but significant, increases in abundance for all ENaC subunits, within 1 h. In conclusion, all three subunits of ENaC are upregulated by vasopressin with temporal and regional differences. These changes are too slow to play a major role in the short-term action of vasopressin to stimulate sodium reabsorption in the collecting duct. Long-term increases in ENaC abundance should add to the short-term regulatory mechanisms (undefined in this study) to enhance sodium transport in the renal collecting duct.

scholarly journals Epithelial Sodium Channel and Salt-Sensitive Hypertension

Hypertension ◽  
2021 ◽  
Vol 77 (3) ◽  
pp. 759-767
Author(s):  
Stephanie M. Mutchler ◽  
Annet Kirabo ◽  
Thomas R. Kleyman
Keyword(s):  
Blood Pressure ◽  
Sodium Channel ◽  
Salt Intake ◽  
Extracellular Fluid ◽  
Pressure Rise ◽  
Epithelial Sodium Channel ◽  
Sodium Reabsorption ◽  
High Salt Intake ◽  
Salt Sensitive Hypertension

The development of high blood pressure is influenced by genetic and environmental factors, with high salt intake being a known environmental contributor. Humans display a spectrum of sodium-sensitivity, with some individuals displaying a significant blood pressure rise in response to increased sodium intake while others experience almost no change. These differences are, in part, attributable to genetic variation in pathways involved in sodium handling and excretion. ENaC (epithelial sodium channel) is one of the key transporters responsible for the reabsorption of sodium in the distal nephron. This channel has an important role in the regulation of extracellular fluid volume and consequently blood pressure. Herein, we review the role of ENaC in the development of salt-sensitive hypertension, and present mechanistic insights into the regulation of ENaC activity and how it may accelerate sodium-induced damage and dysfunction. We discuss the traditional role of ENaC in renal sodium reabsorption and review work addressing ENaC expression and function in the brain, vasculature, and immune cells, and how this has expanded the implications for its role in the initiation and progression of salt-sensitive hypertension.

scholarly journals The Cyp2c44 Epoxygenase Regulates Epithelial Sodium Channel Activity and the Blood Pressure Responses to Increased Dietary Salt

2013 ◽  
Vol 289 (7) ◽  
pp. 4377-4386 ◽  
Author(s):  
Jorge H. Capdevila ◽  
Nataliya Pidkovka ◽  
Shaojun Mei ◽  
Yan Gong ◽  
John R. Falck ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Sodium Channel ◽  
Epithelial Sodium Channel ◽  
Channel Activity ◽  
Dietary Salt ◽  
Blood Pressure Responses

Regulation of blood pressure, the epithelial sodium channel (ENaC), and other key renal sodium transporters by chronic insulin infusion in rats

2006 ◽  
Vol 290 (5) ◽  
pp. F1055-F1064 ◽  
Author(s):  
Jian Song ◽  
Xinqun Hu ◽  
Shahla Riazi ◽  
Swasti Tiwari ◽  
James B. Wade ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Sodium Channel ◽  
Insulin Infusion ◽  
Collecting Duct ◽  
Epithelial Sodium Channel ◽  
Kidney Cortex ◽  
Sodium Reabsorption ◽  
Cortical Collecting Duct ◽  
Sprague Dawley ◽  
Epithelial Sodium Channel Enac

Hyperinsulinemia is associated with hypertension. Dysregulation of renal distal tubule sodium reabsorption may play a role. We evaluated the regulation of the epithelial sodium channel (ENaC) and the thiazide-sensitive Na-Cl cotransporter (NCC) during chronic hyperinsulinemia in rats and correlated these changes to blood pressure as determined by radiotelemetry. Male Sprague-Dawley rats (∼270 g) underwent one of the following three treatments for 4 wk ( n = 6/group): 1) control; 2) insulin-infused plus 20% dextrose in drinking water; or 3) glucose water-drinking (20% dextrose in water). Mean arterial pressures were increased by insulin and glucose (mmHg at 3 wk): 98 ± 1 (control), 107 ± 2 (insulin), and 109 ± 3 (glucose), P < 0.01. Insulin (but not glucose) increased natriuretic response to benzamil (ENaC inhibitor) and hydrochlorothiazide (NCC inhibitor) on average by 125 and 60%, respectively, relative to control rats, suggesting increased activity of these reabsorptive pathways. Neither insulin nor glucose affected the renal protein abundances of NCC or the ENaC subunits (α, β, and γ) in kidney cortex, outer medulla, or inner medulla in a major way, as determined by immunoblotting. However, insulin and to some extent glucose increased apical localization of these subunits in cortical collecting duct principal cells, as determined by immunoperoxidase labeling. In addition, insulin decreased cortical “with no lysine” kinase (WNK4) abundance (by 16% relative to control), which may have increased NCC activity. Overall, insulin infusion increased blood pressure, and NCC and ENaC activity in rats. Increased apical targeting of ENaC and decreased WNK4 expression may be involved.

scholarly journals Conditional Transgenic Mice for Studying the Role of the Glucocorticoid Receptor in the Renal Collecting Duct

Endocrinology ◽  
2008 ◽  
Vol 150 (5) ◽  
pp. 2202-2210 ◽  
Author(s):  
Aurélie Nguyen Dinh Cat ◽  
Antoine Ouvrard-Pascaud ◽  
François Tronche ◽  
Maud Clemessy ◽  
Daniel Gonzalez-Nunez ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Glucocorticoid Receptor ◽  
Sodium Channel ◽  
Leucine Zipper ◽  
Collecting Duct ◽  
Extracellular Volume ◽  
Epithelial Sodium Channel ◽  
Sodium Reabsorption ◽  
Renal Collecting Duct

The mineralocorticoid receptor (MR) is a major regulator of renal sodium reabsorption and body fluid homeostasis. However, little is known about glucocorticoid receptor (GR)-dependent renal effects. Glucocorticoids may activate both receptors, so it is difficult to distinguish between MR- and GR-mediated effects in vivo. To overcome this complexity, we used a transgenic mouse model allowing conditional GR overexpression (doxycycline inducible TetON system, Hoxb7 promoter) in the renal collecting duct (CD) to identify GR-regulated genes involved in sodium transport in the CD. In microdissected cortical CD, induction of GR expression led (after 2 d of doxycycline) to increased α-epithelial sodium channel and glucocorticoid-induced leucine zipper and decreased abundance of with-no-lysine kinase 4 transcripts, without modification of Na,K-ATPase, serum- and glucocorticoid-kinase-1, or MR expression. No changes occurred in the upstream distal and connecting tubules [distal convoluted tubule (DCT), connecting tubule (CNT)]. Sodium excretion was unaltered, but the urinary aldosterone concentration was reduced, suggesting compensation of transitory extracellular volume expansion that subsequently disappeared. At steady state, i.e. after 15 d of doxycycline administration, transcript abundance remained altered in the CD, whereas mirror changes appeared in the DCT and CNT. Plasma aldosterone or glucocorticoids and blood pressure were all unaffected. These experiments show that: 1) GR, in addition to MR, controls epithelial sodium channel- and glucocorticoid-induced leucine zipper expression in vivo in the CD; 2) with-no-lysine kinase 4 is negatively controlled by GR; and 3) the DCT and CNT compensate for these alterations to maintain normal sodium reabsorption and blood pressure. These results suggest that enhanced GR expression may contribute to enhanced sodium retention in some pathological situations.

scholarly journals Epithelial Sodium Channel Is a Key Mediator of Growth Hormone-Induced Sodium Retention in Acromegaly

Endocrinology ◽  
2008 ◽  
Vol 149 (7) ◽  
pp. 3294-3305 ◽  
Author(s):  
Peter Kamenicky ◽  
Say Viengchareun ◽  
Anne Blanchard ◽  
Geri Meduri ◽  
Philippe Zizzari ◽  
...  
Keyword(s):  
Sodium Channel ◽  
Sodium Transport ◽  
Epithelial Sodium Channel ◽  
Janus Kinase ◽  
Sodium Reabsorption ◽  
Sodium Retention ◽  
Signal Transducer ◽  
Distal Nephron ◽  
Igf I ◽  
Gc Rats

Acromegalic patients present with volume expansion and arterial hypertension, but the renal sites and molecular mechanisms of direct antinatriuretic action of GH remain unclear. Here, we show that acromegalic GC rats, which are chronically exposed to very high levels of GH, exhibited a decrease of furosemide-induced natriuresis and an increase of amiloride-stimulated natriuresis compared with controls. Enhanced Na+,K+-ATPase activity and altered proteolytic maturation of epithelial sodium channel (ENaC) subunits in the cortical collecting ducts (CCDs) of GC rats provided additional evidence for an increased sodium reabsorption in the late distal nephron under chronic GH excess. In vitro experiments on KC3AC1 cells, a murine CCD cell model, revealed the expression of functional GH receptors and IGF-I receptors coupled to activation of Janus kinase 2/signal transducer and activator of transcription 5, ERK, and AKT signaling pathways. That GH directly controls sodium reabsorption in CCD cells is supported by: 1) stimulation of transepithelial sodium transport inhibited by GH receptor antagonist pegvisomant; 2) induction of α-ENaC mRNA expression; and 3) identification of signal transducer and activator of transcription 5 binding to a response element located in the α-ENaC promoter, indicative of the transcriptional regulation of α-ENaC by GH. Our findings provide the first evidence that GH, in concert with IGF-I, stimulates ENaC-mediated sodium transport in the late distal nephron, accounting for the pathogenesis of sodium retention in acromegaly.

scholarly journals Cell-specific expression of epithelial sodium channel alpha, beta, and gamma subunits in aldosterone-responsive epithelia from the rat: localization by in situ hybridization and immunocytochemistry.

1994 ◽  
Vol 127 (6) ◽  
pp. 1907-1921 ◽  
Author(s):  
C Duc ◽  
N Farman ◽  
C M Canessa ◽  
J P Bonvalet ◽  
B C Rossier
Keyword(s):  
In Situ Hybridization ◽  
Sodium Channel ◽  
Sodium Transport ◽  
Epithelial Sodium Channel ◽  
Rat Colon ◽  
Sodium Reabsorption ◽  
Gamma Subunit ◽  
Collecting Ducts ◽  
Alpha Beta

A highly selective, amiloride-sensitive, epithelial sodium channel from rat colon (rENaC), composed of three homologous subunits termed alpha, beta, and gamma rENaC, has been cloned by functional expression and was proposed to mediate electrogenic sodium reabsorption in aldosterone-responsive epithelia. To determine whether rENaC could account for sodium absorption in vivo, we studied the cellular localization of the sodium channel messenger RNA subunits by in situ hybridization and their cellular and subcellular distribution by immunocytochemistry in the kidney, colon, salivary, and sweat glands of the rat. In the kidney, we show that the three subunit mRNAs are specifically co-expressed in the renal distal convoluted tubules (DCT), connecting tubules (CNT), cortical collecting ducts (CCD), and outer medullary collecting ducts (OMCD), but not in the inner medullary collecting ducts (IMCD). We demonstrate co-localization of alpha, beta, and gamma subunit proteins in the apical membrane of a majority of cells of CCD and OMCD. Our data indicate that alpha, beta, and gamma subunit mRNAs and proteins are co-expressed in the distal nephron (excepting IMCD), a localization that correlates with the previously described physiological expression of amiloride-sensitive electrogenic sodium transport. Our data, however, suggest that another sodium transport protein mediates electrogenic amiloride-sensitive sodium reabsorption in IMCD. We also localized rENaC to the surface epithelial cells of the distal colon and to the secretory ducts of the salivary gland and sweat gland, providing further evidence consistent with the hypothesis that the highly selective, amiloride-sensitive sodium channel is physiologically expressed in aldosterone-responsive cells.

scholarly journals Activation of the Hypoxia-Inducible Factor Pathway Inhibits Epithelial Sodium Channel-Mediated Sodium Transport in Collecting Duct Principal Cells

2021 ◽  
pp. ASN.2021010046
Author(s):  
Eva Dizin ◽  
Valerie Olivier ◽  
Isabelle Roth ◽  
Ali Sassi ◽  
Grégoire Arnoux ◽  
...  
Keyword(s):  
Sodium Channel ◽  
Knockout Mice ◽  
Sodium Transport ◽  
Sodium Intake ◽  
Collecting Duct ◽  
Epithelial Sodium Channel ◽  
Sodium Reabsorption ◽  
Active Sodium ◽  
Principal Cells ◽  
Hif Pathway

Background Active sodium reabsorption is the major factor influencing renal oxygen consumption and production of reactive oxygen species (ROS). Increased sodium reabsorption uses more oxygen, which may worsen medullary hypoxia and produce more ROS via enhanced mitochondrial ATP synthesis. Both mechanisms may activate the hypoxiainducible factor (HIF) pathway. Because the collecting duct is exposed to low oxygen pressure and variations of active sodium transport, we assessed whether the HIF pathway controls epithelial sodium channel (ENaC)-dependent sodium transport. Methods We investigated HIF's effect on ENaC expression in mpkCCDcl4 cells (a model of collecting duct principal cells) using real-time PCR and Western blot and ENaC activity by measuring amiloride-sensitive current. We also assessed the effect of hypoxia and sodium intake on abundance of kidney sodium transporters in wild-type and inducible kidney tubule-specific Hif1α knockout mice. Results In cultured cells, activation of the HIF pathway by dimethyloxalylglycine or hypoxia inhibited sodium transport and decreased expression of βENaC and γENaC, as well as of Na,K-ATPase. HIF1α silencing increased βENaC and γENaC expression and stimulated sodium transport. A constitutively active mutant of HIF1α produced the opposite effect. Aldosterone and inhibition of the mitochondrial respiratory chain slowly activated the HIF pathway, suggesting that ROS may also activate HIF. Decreased γENaC abundance induced by hypoxia in normal mice was abolished in Hif1α knockout mice. Similarly, Hif1α knockout led to increased γENaC abundance under high sodium intake. Conclusions This study reveals that γENaC expression and activity are physiologically controlled by the HIF pathway, which may represent a negative feedback mechanism to preserve oxygenation and/or prevent excessive ROS generation under increased sodium transport.

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