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Dose response of aldosterone on-ENaC mRNA expression in rat EDC and LDC. A: Northern blots. Epithelia were incubated with aldosterone (aldo; concentrations as indicated) or carrier (ctrl) for 8 h. Blots are representative of 3 Northern blots detecting-subunit in EDC or LDC. B: densitometry. Intensity of-ENaC mRNA expression was normalized to GAPDH. Relative abundance of aldosterone-treated epithelia was expressed in percentage of signal obtained in controls treated with carrier only. Data are given as mean percentages SE determined from at least 3 Northern blots detecting-ENaC mRNA. *P 0.05 vs. control.
Source publication
Aldosterone-induced sodium absorption is mediated by the epithelial Na(+) channel (ENaC). It is thought that the "early effect" is not based on genomic regulation of ENaC expression, because ENaC subunit transcription was reported to start later than Na(+) transport. We investigated electrogenic Na(+) absorption (J(Na)) and, in identical tissues, m...
Context in source publication
Context 1
... increase of -and -ENaC mRNA expression was found in both EDC and LDC ( Fig. 2; P 0.001, n 9). In contrast to earlier in vivo studies (1,21,24), -ENaC was not constitutively expressed in LDC. Instead, in this segment of the distal colon, -ENaC mRNA was downregulated after 8 h of aldosterone incubation (65.7 10% of controls, P 0.05, n 12; Fig. 1C). (Fig. 3). The different expression of -ENaC mRNA in EDC and LDC added to the concept of a segmental heterogeneity within the distal ...
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Citations
... To test whether non-junctional claudins in primary tissue can be detected by cCPE, an ex vivo model of rat colon tissue was used. Colon mucosa was prepared from a rat and cultured in Ussing chambers, and the barrier integrity was monitored by TER measurements [61]. The tissue was incubated with AF647-GST-cCPE fusion proteins for 30 min and subsequently fixed, followed by immunostaining and confocal microscopy for image acquisition. ...
Claudins regulate paracellular permeability, contribute to epithelial polarization and are dysregulated during inflammation and carcinogenesis. Variants of the claudin-binding domain of Clostridium perfringens enterotoxin (cCPE) are highly sensitive protein ligands for generic detection of a broad spectrum of claudins. Here, we investigated the preferential binding of YFP- or GST-cCPE fusion proteins to non-junctional claudin molecules. Plate reader assays, flow cytometry and microscopy were used to assess the binding of YFP- or GST-cCPE to non-junctional claudins in multiple in vitro and ex vivo models of human and rat gastrointestinal epithelia and to monitor formation of a tight junction barrier. Furthermore, YFP-cCPE was used to probe expression, polar localization and dysregulation of claudins in patient-derived organoids generated from gastric dysplasia and gastric cancer. Live-cell imaging and immunocytochemistry revealed cell polarity and presence of tight junctions in glandular organoids (originating from intestinal-type gastric cancer and gastric dysplasia) and, in contrast, a disrupted diffusion barrier for granular organoids (originating from discohesive tumor areas). In sum, we report the use of cCPE fusion proteins as molecular probes to specifically and efficiently detect claudin expression, localization and tight junction dysregulation in cell lines, tissue explants and patient-derived organoids of the gastrointestinal tract.
... Aldosterone controls the expression of target genes either by directly influencing their transcription (e.g., ENaC subunits) [41], or through the action of intermediate kinases (e.g., SGK-1) [42] or ubiquitin ligases (e.g., Nedd4-2) [43]. In many cases, these mechanisms overlap. ...
The corticosteroid hormone, aldosterone, markedly enhances K⁺ secretion throughout the colon, a mechanism critical to its role in maintaining overall K⁺ balance. Previous studies demonstrated that basolateral NKCC1 was up-regulated by aldosterone in the distal colon specifically to support K⁺ secretion—which is distinct from the more well-established role of NKCC1 in supporting luminal Cl⁻ secretion. However, considerable segmental variability exists between proximal and distal colonic ion transport processes, especially concerning their regulation by aldosterone. Furthermore, delineating such region-specific effects has important implications for the management of various gastrointestinal pathologies. Experiments were therefore designed to determine whether aldosterone similarly up-regulates NKCC1 in the proximal colon to support K⁺ secretion. Using dietary Na⁺ depletion as a model of secondary hyperaldosteronism in rats, we found that proximal colon NKCC1 expression was indeed enhanced in Na⁺-depleted (i.e., hyperaldosteronemic) rats. Surprisingly, electrogenic K⁺ secretion was not detectable by short-circuit current (ISC) measurements in response to either basolateral bumetanide (NKCC1 inhibitor) or luminal Ba²⁺ (non-selective K⁺ channel blocker), despite enhanced K⁺ secretion in Na⁺-depleted rats, as measured by ⁸⁶Rb⁺ fluxes. Expression of BK and IK channels was also found to be unaltered by dietary Na⁺ depletion. However, bumetanide-sensitive basal and agonist-stimulated Cl⁻ secretion (ISC) were significantly enhanced by Na⁺ depletion, as was CFTR Cl⁻ channel expression. These data suggest that NKCC1-dependent secretory pathways are differentially regulated by aldosterone in proximal and distal colon. Development of therapeutic strategies in treating pathologies related to aberrant colonic K⁺/Cl⁻ transport—such as pseudo-obstruction or ulcerative colitis—may benefit from these findings.
... α-ENaC is constitutively expressed, whereas β-and γ-ENaC expression is regulated by gluco-and mineralocorticoids [12]. Enhanced Na + absorption via activated ENaC in the distal colon is accompanied by transcriptional up-regulation of β-and γ-ENaC-subunits [13,14]. ...
The epithelial sodium channel (ENaC) can increase the colonic absorptive capacity for salt and water. Campylobacter concisus is a common pathogenic epsilonproteobacterium, causing enteritis and diarrhea. It can induce barrier dysfunction in the intestine, but its influence on intestinal transport function is still unknown. Therefore, our study aimed to characterize C. concisus effects on ENaC using the HT-29/B6-GR/MR (epithelial cell line HT-29/B6 transfected with glucocorticoid and mineralocorticoid receptors) cell model and mouse colon. In Ussing chambers, C. concisus infection inhibited ENaC-dependent Na+ transport as indicated by a reduction in amiloride-sensitive short circuit current (−55%, n = 15, p < 0.001). This occurred via down-regulation of β- and γ-ENaC mRNA expression and ENaC ubiquitination due to extracellular signal-regulated kinase (ERK)1/2 activation, predicted by Ingenuity Pathway Analysis (IPA). In parallel, C. concisus reduced the expression of the sealing tight junction (TJ) protein claudin-8 and induced claudin-8 redistribution off the TJ domain of the enterocytes, which facilitates the back leakage of Na+ ions into the intestinal lumen. In conclusion, C. concisus caused ENaC dysfunction via interleukin-32-regulated ERK1/2, as well as claudin-8-dependent barrier dysfunction—both of which contribute to Na+ malabsorption and diarrhea.
... sweat gland ductal cells, cortical collecting duct, colon, etc.) is the expression and/or insertion of ENaC into the luminal membrane via aldosterone (González-Montelongo et al., 2016). In many of these cell types it has been shown that aldosterone causes the rapid expression of ENaC within 2-6 h (Alvarez de la Rosa et al., 2002;Epple et al., 2000;Loffing et al., 2001). Furthermore, in rats implanted with osmotic minipumps to deliver aldosterone at a constant rate it was found that sodium ion reabsorption in the kidney was significantly increased 60% after 4 h of infusion (Ergonul et al., 2006). ...
The purpose of this study was to determine the time course for the previously reported reduction in sweat sodium ion concentration during heat acclimation. Four healthy volunteers completed 7 consecutive days of heat acclimation which included 2h of treadmill walking in a 40°C and 40% relative humidity environment. A modified constant hyperthermia protocol was used as workloads were increased each day to maintain a constant core temperature over the 7 days of heat acclimation. Forearm sweat was collected 3 times during each 2h exercise bout on days 1, 3, 5, and 7 of heat acclimation. Forearm sweat rate and sweat sodium ion concentration were determined from each sample. The results showed that there was a significant (p < 0.05) downward shift in the mean sweat rate vs. sweat sodium ion concentration relationship on days 3, 5, and 7 of heat acclimation, as compared to the pre-heat acclimation (day 1) data. Thus, at any given sweat rate, heat acclimation resulted in a significantly lower sweat sodium ion concentration. The response was very rapid and occurred following only 2 consecutive days of heat exposure (i.e., day 3 vs. day 1 data). Furthermore, the calculated sweat sodium ion concentration, at a sweat rate of 1μl/cm²/min, decreased linearly (r = - 0.50, p < 0.05) during the 7 days of heat acclimation. Such results suggest that heat acclimation rapidly improves sodium ion reabsorption from the eccrine sweat gland duct as evidenced by significant reductions in the sweat sodium ion concentration.
... It is known that aldosterone stimulates Na + absorption in collecting ducts by increasing ENaC protein expression [228,229] and mRNA levels [229,230]. Aldosterone also increases the activity of ENaC through a MR classical aldosteroneinduced activation, which is mediated by SGK1 [231][232][233][234]. Aldosterone-induced SGK1 mRNA level increase occurs within 30 min, a remarkably fast transcriptional response of aldosterone [27], which seems to involve ubiquitylation and/ or deubiquitylation processes [235,236]. ...
Aldosterone is the most known mineralocorticoid hormone synthesized by the adrenal cortex. The genomic pathway displayed by aldosterone is attributed to the mineralocorticoid receptor (MR) signaling. Even though the rapid effects displayed by aldosterone are long known, our knowledge regarding the receptor responsible for such event is still poor. It is intense that the debate whether the MR or another receptor—the “unknown receptor”—is the receptor responsible for the rapid effects of aldosterone. Recently, G protein-coupled estrogen receptor-1 (GPER-1) was elegantly shown to mediate some aldosterone-induced rapid effects in several tissues, a fact that strongly places GPER-1 as the unknown receptor. It has also been suggested that angiotensin receptor type 1 (AT1) also participates in the aldosterone-induced rapid effects. Despite this open question, the relevance of the beneficial effects of aldosterone is clear in the kidneys, colon, and CNS as aldosterone controls the important water reabsorption process; on the other hand, detrimental effects displayed by aldosterone have been reported in the cardiovascular system and in the kidneys. In this line, the MR antagonists are well-known drugs that display beneficial effects in patients with heart failure and hypertension; it has been proposed that MR antagonists could also play an important role in vascular disease, obesity, obesity-related hypertension, and metabolic syndrome. Taken altogether, our goal here was to (1) bring a historical perspective of both genomic and rapid effects of aldosterone in several tissues, and the receptors and signaling pathways involved in such processes; and (2) critically address the controversial points within the literature as regarding which receptor participates in the rapid pathway display by aldosterone.
... This is compatible with the different embryological origins and physiology of proximal and distal tumours (Iacopetta, 2002) as well as with differences in molecular and genetic characteristics of the two segments (Iacopetta, 2002;Birkenkamp-Demtroder et al, 2005;Leopoldo et al, 2008). In the present context, ENaC displays a significant gradient of expression and activity towards distal colon in rodents (Epple et al, 2000;Greig et al, 2002). Whether a similar gradient is present in humans is unknown. ...
Background:
Lithium accumulates in the colon and inhibits the enzyme GSK-3β that possesses anti-carcinogenic effects. We therefore examined the association between lithium use and colorectal cancer risk in a nationwide study.
Methods:
We used the Danish Cancer Registry to identify all patients diagnosed with incident colorectal adenocarcinoma during 2000-2012 (n=36 248). Using a matched case-control approach, we estimated the association between long-term use (⩾5 years) of lithium and risk of colorectal adenocarcinoma using conditional logistic regression.
Results:
Long-term use of lithium was similar among cases (0.22%) and controls (0.20%), yielding an odds ratio of 1.13 (95% confidence interval (CI), 0.89-1.43) for colorectal adenocarcinoma. Dose-response, subgroup and other subanalyses returned neutral associations. However, ORs differed for colorectal subsites (proximal colon: 1.01 (95% CI, 0.66-1.55; distal colon: 1.52 (95% CI, 1.05-2.20); and rectum: 0.80 (95% CI, 0.50-1.30).
Conclusions:
Lithium use was not associated with an overall increased risk of colorectal adenocarcinoma. The variation by subsite warrants further investigation.British Journal of Cancer advance online publication, 11 February 2016; doi:10.1038/bjc.2016.10 www.bjcancer.com.
... Aldosterone induces the expression of b-subunits and g-subunits to assemble a fully operational ENaC channel in the apical colonocyte membrane with constitutively expressed a-subunits. 8 The epithelial Na + channel-mediated electrogenic Na + transport is regulated via mineralocorticoid action depending on the salt and fluid homeostasis and is upregulated in conditions with severe electrolyte and fluid loss. 9,10 However, we and others have shown in murine models and in man that in conditions of colonic inflammation, such as inflammatory bowel disease, ENaC can be impaired through proinflammatory cytokines. ...
... Epithelial Na + channel-dependent Na + absorption is induced by transcriptional upregulation of the ENaC b-subunit and g-subunit in response to aldosterone. 8,11 Thus, the reduced maximum transport capacity of J Na in LC might be due to a lack of transcriptional induction of the ENaC subunits. Therefore, a-ENaC, b-ENaC, and g-ENaC mRNA were quantified by realtime PCR in biopsy specimens that were stimulated for 8 hours with aldosterone in the Ussing chamber and were then compared with non-aldosterone-stimulated biopsies of the same patient that were also maintained in the Ussing chamber for 8 hours. ...
... Epithelial Na + channel regulation in rat distal colon closely resembles that of human sigmoid colon and allows, in contrast to human biopsies, for long-term cytokine pre-exposure experiments in Ussing chambers with tissue viabilities superior to human biopsy specimens. 8,11,12 For these experiments, a cocktail with TNFa, IFNg, and IL-15 was used. Six hours preexposure with IFN-g, IL-15, and TNFa (before the addition of aldosterone) (see Figure 1C, Supplemental Digital Content 1, http://links.lww.com/IBD/B165) ...
Background:
Lymphocytic colitis (LC) causes watery diarrhea. We aimed to identify mechanisms of altered Na absorption and regulatory inputs in patients with LC by examining the epithelial Na channel (ENaC) function as the predominant Na transport system in human distal colon.
Methods:
Epithelial Na channel function and regulation was analyzed in biopsies from sigmoid colon of patients with LC and in rat distal colon in Ussing chambers. ENaC-subunit expression was measured by real-time PCR and RNA sequencing. Correction factors for subepithelial resistance contributions were determined by impedance spectroscopy. Upstream regulators in LC were determined by RNA sequencing.
Results:
Epithelial Na channel-mediated electrogenic Na transport was inhibited despite aldosterone stimulation in human sigmoid colon of patients with LC. The increase in γ-ENaC mRNA expression in response to aldosterone was MEK1/2-dependently reduced in LC, since it could be restored toward normal by MEK1/2 inhibition through U0126. Parallel experiments for identification of signaling in rat distal colon established MEK1/2 to be activated by a cytokine cocktail of TNFα, IFNγ, and IL-15, which were identified as the most important regulators in the upstream regulator analysis in LC.
Conclusions:
In the sigmoid colon of patients with LC, the key effector cytokines TNFα, IFNγ, and IL-15 inhibited γ-ENaC upregulation in response to aldosterone through a MEK1/2-mediated pathway. This prevents ENaC to reach its maximum transport capacity and results in Na malabsorption which contributes to diarrhea.
... Sodium deprivation increases expression of both β and γ subunits of the epithelial sodium channel (ENaC) in rat distal colon. 13 Interestingly, rat rectal epithelium shows amiloride-sensitive sodium transport even in rats tilled water. The high-sodium group received the same diet than the control group, but the drinking fluid was saline (0.9 g/dl sodium chloride; 154 µmol of sodium per milliliter). ...
... 12 An aldosterone concentration of 3 nM has been found quite effective to induce electrogenic transport in the rat rectal colon in vitro. 12,13 However, for the experiments reported here we chose to incubate the tissues with aldosterone at 10 nM (as Inagaki et al 14 did), a concentration that still is within the range of physiological response. 9,12 One reason for this modification was that preliminary experiments showed that the response to incubation with 3 nM aldosterone was quite variable under our experimental conditions. ...
... As it could have been expected from previous reports, [12][13][14] amiloride drastically decreased I SC and QO 2 after incubation with aldosterone. In this case, the de-creases were larger in the sodium-deprived group. ...
Introduction:
The colonic epithelium is a classical aldosterone target, but the effect of the hormone on the oxygen consumption rate (QO2 ) of this tissue is unknown. Objectives. We aimed at assessing, in the rectal epithelium of rats fed with diets of different sodium content, the effect of epithelial sodium channel (ENaC) blockade on short-circuit current (ISC ) and QO2 , and the acute effect of aldosterone incubation on ISC and QO2 .
Methods:
Adult male rats were fed with normal, low or high-sodium diets for 8 days. Plasma sodium and serum aldosterone were measured. Isolated mucosa preparations from the rectal portion of the colon were mounted in Ussing chambers modified to measure ISC and QO2.
Results:
Baseline ISC and QO2 were highest in sodium-deprived rats. Both were proportionally reduced by amiloride (0.1 mM) in this group and in the normal sodium group, but not in sodium-loaded rats. In separate experiments, incubation with aldosterone (10 nM) for 7 h increased ISC and QO2 in all groups; increases were larger in the normal and sodium-loaded groups. Amiloride decreased both ISC and QO2 , abolishing the differences between groups. Linear regression of the decrease in QO2 and ISC after amiloride showed the steepest slope for the sodium-deprived group and the flattest one for the sodium-loaded group.
Conclusions:
Baseline epithelial QO2 of sodium-deprived and control rats is reduced by ENaC blockade. Aldosterone increased QO2 proportionally to ISC augmentation in all groups, but the coupling between aerobic metabolism and electrogenic transport seems more efficient in sodium-deprived animals.
... At a molecular level, ENaC is usually assumed to be a heterotrimer of one α-subunit, one β-subunit and one γ-subunit (Jasti et al. 2007;Firsov et al. 1998). In contrast to other steroid-responsive organs, such as lung and distal nephron, in the distal colon only the βand γ-subunits are regulated, while the α-subunit is constitutively expressed (Renard et al. 1995;Epple et al. 2000). In addition, ENaC-dependent Na + transport is regulated by increased recruitment as well as prolonged insertion of active channels into the apical enterocyte membrane (Greig et al. 2004). ...
... Under those conditions, ENaC is abundantly expressed and located in the apical membrane of enterocytes as the result of steroid action. Although different cellular processes, such as reduced ubiquitination, contribute to this up-regulation of ENaC activity, we and others have previously shown that regulation occurs to a significant extent via transcriptional induction of βand γ-ENaC subunits, while the α-ENaC subunit is constitutively expressed (Renard et al. 1995;Epple et al. 2000). ...
... Technical terms used in this figure are also listed in the abbreviations. J Physiol 593.24 process for ENaC induction in the intestine (Epple et al. 2000). As also postulated for other STAT proteins (Stocklin et al. 1996), Biola et al. reported that in murine T-lymphocytes, STAT6 and GR interact to mutually antagonize transactivation (Biola et al. 2000). ...
Key points:
Interleukin-13 (IL-13) causes intestinal epithelial barrier dysfunction, and is implicated in the pathogenesis of Th2-driven intestinal inflammation (e.g. ulcerative colitis). However, it is unclear whether the epithelial sodium channel (ENaC) - the main limiting factor for sodium absorption in the distal colon - is also influenced by IL-13 and if so, by what mechanism(s). We demonstrate in an intestinal cell model as well as in mouse distal colon that IL-13 causes reduced ENaC activity. We show that IL-13 impairs ENaC-dependent sodium transport by activating the JAK1/2-STAT6 signalling pathway. These results improve our understanding of the mechanisms through which IL-13 functions as a key effector cytokine in ulcerative colitis, thereby contributing to the distinct pathology of this disease.
Abstract:
Interleukin-13 (IL-13) has been strongly implicated in the pathogenesis of ulcerative colitis, possibly by disrupting epithelial integrity. In the distal colon, the epithelial sodium channel (ENaC) is an important factor in the regulation of sodium absorption, and therefore plays a critical role in minimizing intestinal sodium and water losses. In the present study, we investigated whether IL-13 also acts as a potent modulator of epithelial sodium transport via ENaC, and the signalling components involved. The effect of IL-13 on ENaC was examined in HT-29/B6-GR/MR human colon cells, as well as in mouse distal colon, by measuring amiloride-sensitive short-circuit current (ISC ) in Ussing chambers. The expression levels of ENaC subunits and the cellular components that contribute to ENaC activity were analysed by qRT-PCR and promoter gene assay. We show that IL-13, in both the cell model and in native intestinal tissue, impaired epithelial sodium absorption via ENaC (JNa ) as a result of decreased transcription levels of β- and γ-ENaC subunits and SGK1, a post-translational regulator of ENaC activity, due to impaired promoter activity. The reduction in JNa was prevented by inhibition of JAK1/2-STAT6 signalling. This inhibition also affected the IL-13-induced decrease in p38 MAPK phosphorylation. The contribution of STAT6 to IL-13-mediated ENaC inactivation was confirmed in a STAT6(-/-) mouse model. In conclusion, these results indicate that IL-13, the levels of which are elevated in ulcerative colitis, contributes to impaired ENaC activity via modulation of the STAT6/p38 MAPK pathways.
... An electrogenic Na + reabsorption mediated by ENaC is restricted to the colon and the rectum. ENaC in the distal colon is under mineralocorticoid and glucocorticoid control: both aldosterone and dexamethasone control the abundance of b and g but not a mRNA transcripts (Epple et al., 2000;Fuller et al., 2000). Mice lacking the a ENaC subunit in colonic superficial cells (SCNN1A-KO) are viable without perinatal lethality, in contrast to mice lacking aENaC in the kidney, but show salt loss and mineralocorticoid resistance, indicating that Na + absorption in the kidney can compensate for the absence of ENaC-mediated Na + absorption in the colon (Malsure et al., 2014). ...
... Aldosterone is the major regulator of ENaC in the ASDN. Aldosterone increases the synthesis of a ENaC but not of b or g ENaC in the kidney, in contrast to the colon where aldosterone or dexamethasone increase the synthesis of b and g only (Masilamani et al., 1999;Epple et al., 2000;Fuller et al., 2000;Loffing et al., 2000b). This increase in the synthesis of a ENaC is accompanied by the redistribution of the ENaC subunits from an intracellular pool to the apical membrane of principal cells. ...
The epithelial Na(+) channel (ENaC) and the acid-sensing ion channels (ASICs) form subfamilies within the ENaC/degenerin family of Na(+) channels. ENaC mediates transepithelial Na(+) transport, thereby contributing to Na(+) homeostasis and the maintenance of blood pressure and the airway surface liquid level. ASICs are H(+)-activated channels found in central and peripheral neurons, where their activation induces neuronal depolarization. ASICs are involved in pain sensation, the expression of fear, and neurodegeneration after ischemia, making them potentially interesting drug targets. This review summarizes the biophysical properties, cellular functions, and physiologic and pathologic roles of the ASIC and ENaC subfamilies. The analysis of the homologies between ENaC and ASICs and the relation between functional and structural information shows many parallels between these channels, suggesting that some mechanisms that control channel activity are shared between ASICs and ENaC. The available crystal structures and the discovery of animal toxins acting on ASICs provide a unique opportunity to address the molecular mechanisms of ENaC and ASIC function to identify novel strategies for the modulation of these channels by pharmacologic ligands.
