The Interaction of Glucocorticoids and Progesterone Distinctively Affects Epithelial Sodium Transport

Schmidt, Carolin; Klammt, J; Thomé, Ulrich; Laube, Mandy

doi:10.1007/s00408-014-9640-3

Cited by 11 publications

(18 citation statements)

References 49 publications

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“…In contrast, a previous study demonstrated a negative effect of androgens on GR mRNA and protein levels, but in whole lung tissue [32]. Female sex steroids had no influence on fetal pulmonary GR mRNA expression, while the mRNA expression of the estrogen receptor-β and the progesterone receptor has been observed in FDLE cells [33]. In contrast to our results, the total number of lung GR and the measured binding affinity did not significantly differ between male and female sheep fetuses [34].…”

Section: Discussioncontrasting

confidence: 71%

Glucocorticoids Equally Stimulate Epithelial Na+ Transport in Male and Female Fetal Alveolar Cells

Laube

Riedel

Ackermann

et al. 2019

IJMS

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Preterm infants frequently suffer from respiratory distress syndrome (RDS), possibly due to lower expression of epithelial Na+ channels (ENaC). RDS incidence is sex-specific, affecting males almost twice as often. Despite the use of antenatal glucocorticoids (GCs), the sex difference persists. It is still controversial whether both sexes benefit equally from GCs. We previously showed that Na+ transport is higher in female compared with male fetal distal lung epithelial (FDLE) cells. Since GCs increase Na+ transport, we hypothesized that their stimulating effect might be sex-specific. We analyzed FDLE cells with Ussing chambers and RT-qPCR in the presence or absence of fetal serum. In serum-free medium, GCs increased the ENaC activity and mRNA expression, independent of sex. In contrast, GCs did not increase the Na+ transport in serum-supplemented media and abolished the otherwise observed sex difference. Inhibition of the GC receptor in the presence of serum did not equalize Na+ transport between male and female cells. The GC-induced surfactant protein mRNA expression was concentration and sex-specific. In conclusion, female and male FDLE cells exhibit no sex difference in response to GCs with regard to Na+ transport, and GR activity does not contribute to the higher Na+ transport in females.

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Section: Discussioncontrasting

confidence: 71%

Glucocorticoids Equally Stimulate Epithelial Na+ Transport in Male and Female Fetal Alveolar Cells

Laube

Riedel

Ackermann

et al. 2019

IJMS

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“…Dexamethasone concentrations above 100 nM did not further decrease Cftr expression. Noteworthy, a lower effect of higher dexamethasone concentrations on ENaC mRNA expression has been described before [ 25 ]. The response to GC treatment occurred within hours of exposure and a down-regulation of Cftr expression was detected only 6 h after dexamethasone addition.…”

Section: Discussionmentioning

confidence: 92%

Glucocorticoids Distinctively Modulate the CFTR Channel with Possible Implications in Lung Development and Transition into Extrauterine Life

Laube¹,

Bossmann²,

Thomé³

2015

PLoS ONE

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During fetal development, the lung is filled with fluid that is secreted by an active Cl- transport promoting lung growth. The basolateral Na+,K+,2Cl- cotransporter (NKCC1) participates in Cl- secretion. The apical Cl- channels responsible for secretion are unknown but studies suggest an involvement of the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR is developmentally regulated with a high expression in early fetal development and a decline in late gestation. Perinatal lung transition is triggered by hormones that stimulate alveolar Na+ channels resulting in fluid absorption. Little is known on how hormones affect pulmonary Cl- channels. Since the rise of fetal cortisol levels correlates with the decrease in fetal CFTR expression, a causal relation may be assumed. The aim of this study was to analyze the influence of glucocorticoids on pulmonary Cl- channels. Alveolar cells from fetal and adult rats, A549 cells, bronchial Calu-3 and 16HBE14o- cells, and primary rat airway cells were studied with real-time quantitative PCR and Ussing chambers. In fetal and adult alveolar cells, glucocorticoids strongly reduced Cftr expression and channel activity, which was prevented by mifepristone. In bronchial and primary airway cells CFTR mRNA expression was also reduced, whereas channel activity was increased which was prevented by LY-294002 in Calu-3 cells. Therefore, glucocorticoids strongly reduce CFTR expression while their effect on CFTR activity depends on the physiological function of the cells. Another apical Cl- channel, anoctamin 1 showed a glucocorticoid-induced reduction of mRNA expression in alveolar cells and an increase in bronchial cells. Furthermore, voltage-gated chloride channel 5 and anoctamine 6 mRNA expression were increased in alveolar cells. NKCC1 expression was reduced by glucocorticoids in alveolar and bronchial cells alike. The results demonstrate that glucocorticoids differentially modulate pulmonary Cl- channels and are likely causing the decline of CFTR during late gestation in preparation for perinatal lung transition.

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“…To elucidate potential mechanisms, mRNA expression of female sex steroid receptors, estrogen receptor β (ER-β) and progesterone receptor (PR-A/B), were measured after 4 days in culture. We have previously shown that FDLE cells do not express ER-α and PR-B, and products amplified with PR-A/B primers therefore represent mRNA expression of PR-A in FDLE cells [ 18 , 42 , 43 ]. The mRNA expression analysis showed significantly higher levels for ER-β (2.5-fold; p<0.01) and PR-A (1.8-fold; p<0.05) in cells of female origin ( Fig 5 ).…”

Section: Resultsmentioning

confidence: 99%

“…Since FDLE cells do not express ER-α we focused on ER-β whose expression in FDLE cells has been demonstrated before [ 18 , 42 ]. Furthermore, we analyzed the expression of PR in FDLE cells which have been shown to express PR-A only [ 43 ]. Results demonstrated higher mRNA levels for ER-β and PR in female FDLE cells, both directly after cell isolation and after 4 days in culture.…”

Section: Discussionmentioning

confidence: 99%

Male Sex is Associated with a Reduced Alveolar Epithelial Sodium Transport

Kaltofen¹,

Haase²,

Thomé³

et al. 2015

PLoS ONE

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Respiratory distress syndrome (RDS) is the most frequent pulmonary complication in preterm infants. RDS incidence differs between genders, which has been called the male disadvantage. Besides maturation of the surfactant system, Na+ transport driven alveolar fluid clearance is crucial for the prevention of RDS. Na+ transport is mediated by the epithelial Na+ channel (ENaC) and the Na,K-ATPase, therefore potential differences in their expression or activity possibly contribute to the gender imbalance observed in RDS. Fetal distal lung epithelial (FDLE) cells of rat fetuses were separated by sex and analyzed regarding expression and activity of the Na+ transporters. Ussing chamber experiments showed a higher baseline short-circuit current (ISC) and amiloride-sensitive ΔISC in FDLE cells of female origin. In addition, maximal amiloride-sensitive ΔISC and maximal ouabain-sensitive ΔISC of female cells were higher when measured in the presence of a permeabilized basolateral or apical membrane, respectively. The number of FDLE cells per fetus recoverable during cell isolation was also significantly higher in females. In addition, lung wet-to-dry weight ratio was lower in fetal and newborn female pups. Female derived FDLE cells had higher mRNA levels of the ENaC- and Na,K-ATPase subunits. Furthermore, estrogen (ER) and progesterone receptor (PR) mRNA levels were higher in female cells, which might render female cells more responsive, while concentrations of placenta-derived sex steroids do not differ between both genders during fetal life. Inhibition of ER-β abolished the sex differences in Na+ transport and female cells were more responsive to estradiol stimulation. In conclusion, a higher alveolar Na+ transport, possibly attributable to a higher expression of hormone receptors in female FDLE cells, provides an explanation for the well known sex-related difference in RDS occurrence and outcome.

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The Interaction of Glucocorticoids and Progesterone Distinctively Affects Epithelial Sodium Transport

Abstract: Glucocorticoids and progesterone individually increase ENaC mRNA expression; however, the combination of both hormones decreases the stimulatory effects of dexamethasone on Na(+) transport and ENaC mRNA expression.

Cited by 11 publications

References 49 publications

Glucocorticoids Equally Stimulate Epithelial Na+ Transport in Male and Female Fetal Alveolar Cells

Glucocorticoids Equally Stimulate Epithelial Na+ Transport in Male and Female Fetal Alveolar Cells

Glucocorticoids Distinctively Modulate the CFTR Channel with Possible Implications in Lung Development and Transition into Extrauterine Life

Male Sex is Associated with a Reduced Alveolar Epithelial Sodium Transport

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