Glucocorticoid receptor is indispensable for physiological responses to aldosterone in epithelial Na+ channel induction via the mineralocorticoid receptor in a human colonic cell line

Bergann, Theresa; Fromm, Anja; Borden, Steffen A.; Fromm, Michael; Schulzke, Jörg D.

doi:10.1016/j.ejcb.2011.01.001

Cited by 22 publications

(20 citation statements)

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“…In HT‐29/B6‐GR/MR cell monolayers (a novel, highly differentiated colon cell model) stably transfected with the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) (Bergann et al . ), we demonstrated that intestinal sodium absorption via ENaC was significantly affected by IL‐13, a change which reflected defective up‐regulation of ENaC β‐ and γ‐subunits. Using inhibitors to differentiate between MAPK and JAK/STAT6 pathways, and STAT6‐deficient (STAT6 −/− ) mice, we found that IL‐13‐dependent dysregulation of ENaC relied on both MAPK (p38) and STAT6 signalling.…”

Section: Introductionmentioning

confidence: 76%

“…HT‐29/B6‐GR/MR cells, a subclone of the human colorectal cancer cell line HT‐29 (Bergann et al . ), were cultured at 37°C in humidified 95% air/5% CO 2 in 25 cm 2 culture flasks in RPMI1640 medium supplemented with 10% fetal calf serum (FCS, Sigma‐Aldrich Chemie GmbH, Munich, Germany), 1% penicillin–streptomycin (Sigma‐Aldrich), 500 IU ml −1 G418 (Biochrom GmbH, Berlin, Germany) and 200 μg ml −1 hygromycin B (Life Technologies GmbH, Darmstadt, Germany). For most of the experiments cells were seeded on Millicell PCF filters (3 μm; Millipore, Schwalbach, Germany) and grown for 7 days.…”

Section: Methodsmentioning

confidence: 99%

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Interleukin‐13 affects the epithelial sodium channel in the intestine by coordinated modulation of STAT6 and p38 MAPK activity

Dames

Bergann

Fromm

et al. 2015

The Journal of Physiology

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Key pointsr 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).r We demonstrate in an intestinal cell model as well as in mouse distal colon that IL-13 causes reduced ENaC activity.r We show that IL-13 impairs ENaC-dependent sodium transport by activating the JAK1/2-STAT6 signalling pathway.r 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 (I SC ) 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 (J Na ) 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 J Na 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.Please note that Figures 1, 3, 4, 5 and 6 that appear in this final copy-edited version have been updated since the paper was published online as an Accepted Article. The new figures have been supplied by the authors and have been approved by the Editor. The conclusions of the study remain the same. Abbreviations DBA, dexamethasone plus butyrate and aldosterone; ENaC, epithelial sodium channel; GR, glucocorticoid receptor; GRE, glucocorticoid response element; HRE, hormone response element; IL-13, interleukin-13; I SC , amiloride sensitive short-circuit current; J Na , epithelial sodium absorption via the ENaC; MAPK, mitoge...

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Section: Introductionmentioning

confidence: 76%

Section: Methodsmentioning

confidence: 99%

Interleukin‐13 affects the epithelial sodium channel in the intestine by coordinated modulation of STAT6 and p38 MAPK activity

Dames

Bergann

Fromm

et al. 2015

The Journal of Physiology

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“…The GR signal was restored in most nephron segments but not in the ASDN. Furthermore, in a colonic cell line expressing both receptors (an unusual phenomenon in epithelial cell lines), GR activation did not itself induce ENaC but was a prerequisite for the full MR-mediated response to aldosterone (Bergann et al 2011). Similar findings have been reported in neuronal cell lines (Tsugita et al 2009).…”

Section: Figure 2 Glucocorticoid Signal Transduction Apparatusmentioning

confidence: 99%

Glucocorticoids and renal Na⁺ transport: implications for hypertension and salt sensitivity

Hunter

Ivy

Bailey

2014

The Journal of Physiology

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The clinical manifestations of glucocorticoid excess include central obesity, hyperglycaemia, dyslipidaemia, electrolyte abnormalities and hypertension. A century on from Cushing's original case study, these cardinal features are prevalent in industrialized nations. Hypertension is the major modifiable risk factor for cardiovascular and renal disease and reflects underlying abnormalities of Na+ homeostasis. Aldosterone is a master regulator of renal Na+ transport but here we argue that glucocorticoids are also influential, particularly during moderate excess. The hypothalamic–pituitary–adrenal axis can affect renal Na+ homeostasis on multiple levels, systemically by increasing mineralocorticoid synthesis and locally by actions on both the mineralocorticoid and glucocorticoid receptors, both of which are expressed in the kidney. The kidney also expresses both of the 11β-hydroxysteroid dehydrogenase (11βHSD) enzymes. The intrarenal generation of active glucocorticoid by 11βHSD1 stimulates Na+ reabsorption; failure to downregulate the enzyme during adaption to high dietary salt causes salt-sensitive hypertension. The deactivation of glucocorticoid by 11βHSD2 underpins the regulatory dominance for Na+ transport of mineralocorticoids and defines the ‘aldosterone-sensitive distal nephron’. In summary, glucocorticoids can stimulate renal transport processes conventionally attributed to the renin–angiotensin–aldosterone system. Importantly, Na+ and volume homeostasis do not exert negative feedback on the hypothalamic–pituitary–adrenal axis. These actions are therefore clinically relevant and may contribute to the pathogenesis of hypertension in conditions associated with elevated glucocorticoid levels, such as the metabolic syndrome and chronic stress.

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“…However, all cells expressing MR coexpress GR, and it has been shown that both receptors can form heterodimers that may participate in aldosterone-mediated gene regulation. In the late distal colon there are data suggesting that MR and GR act cooperatively to increase transepithelial Na ϩ transport in response to aldosterone (5,25). Therefore, we tested whether selective pharmacological blockade of MR or GR affected hnRNP A2/B1 induction by aldosterone in the rat distal colon.…”

Section: Discussionmentioning

confidence: 97%

Heterogeneous nuclear ribonucleoprotein A2/B1 is a tissue-specific aldosterone target gene with prominent induction in the rat distal colon

Giráldez

Morales

Hernández

et al. 2013

American Journal of Physiology-Gastrointestinal and Liver Physi

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The steroid hormone aldosterone enhances transepithelial Na(+) reabsorption in tight epithelia and is crucial to achieve extracellular volume homeostasis and control of blood pressure. One of the main transport pathways regulated by aldosterone involves the epithelial Na(+) channel (ENaC), which constitutes the rate-limiting step of Na(+) reabsorption in parts of the distal nephron and the collecting duct, the distal colon, and sweat and salivary glands. Although these epithelial tissues share the same receptor for aldosterone (mineralocorticoid receptor, MR), and the same transport system (ENaC), it has become clear that the molecular mechanisms involved in the modulation of channel activity are tissue-specific. Recent evidence suggests that aldosterone controls transcription and also translation of ENaC subunits in some cell types. A possible pathway for translational regulation is binding of regulatory proteins to ENaC subunit mRNAs, such as the heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNP A2/B1). In this study, we examined whether hnRNP A2/B1 is an aldosterone-target gene in vivo. Our data show that physiological levels of aldosterone markedly induce hnRNP A2/B1 expression in an early and sustained manner in the late distal colon epithelium but not in other aldosterone-target tissues. The effect depends on MR but not on glucocorticoid receptor activity. We also demonstrate that the genomic region upstream of hnRNP A2/B1 contains aldosterone-responsive elements involved in the control of gene expression. We hypothesize that hnRNP A2/B1 is involved in the tissue-specific regulation of ENaC biosynthesis and may coordinate the response of other genes relevant for transepithelial Na(+) reabsorption by aldosterone.

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Glucocorticoid receptor is indispensable for physiological responses to aldosterone in epithelial Na+ channel induction via the mineralocorticoid receptor in a human colonic cell line

Cited by 22 publications

References 27 publications

Interleukin‐13 affects the epithelial sodium channel in the intestine by coordinated modulation of STAT6 and p38 MAPK activity

Interleukin‐13 affects the epithelial sodium channel in the intestine by coordinated modulation of STAT6 and p38 MAPK activity

Glucocorticoids and renal Na⁺ transport: implications for hypertension and salt sensitivity

Heterogeneous nuclear ribonucleoprotein A2/B1 is a tissue-specific aldosterone target gene with prominent induction in the rat distal colon

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Glucocorticoid receptor is indispensable for physiological responses to aldosterone in epithelial Na+ channel induction via the mineralocorticoid receptor in a human colonic cell line

Cited by 22 publications

References 27 publications

Interleukin‐13 affects the epithelial sodium channel in the intestine by coordinated modulation of STAT6 and p38 MAPK activity

Interleukin‐13 affects the epithelial sodium channel in the intestine by coordinated modulation of STAT6 and p38 MAPK activity

Glucocorticoids and renal Na+ transport: implications for hypertension and salt sensitivity

Heterogeneous nuclear ribonucleoprotein A2/B1 is a tissue-specific aldosterone target gene with prominent induction in the rat distal colon

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Glucocorticoids and renal Na⁺ transport: implications for hypertension and salt sensitivity