Abstract
BackgroundGlucocorticoid hormones play a major role in fetal organ maturation. Yet, excessive glucocorticoid exposure in utero can result in a variety of detrimental effects, such as growth retardation and increased susceptibility to the development of hypertension. To protect the fetus, maternal glucocorticoids are metabolized into inactive compounds by placental 11beta-hydroxysteroid dehydrogenase type2 (11βHSD2). This enzyme is also expressed in the kidney, where it prevents illicit occupation of the mineralocorticoid receptor by glucocorticoids. We investigated the role of renal 11βHSD2 in the control of neonatal glucocorticoid metabolism in the human and mouse.MethodsCortisol (F) and cortisone (E) concentrations were measured in maternal plasma, umbilical cord blood and human newborn urine using HPLC. 11βHSD2 activity was indirectly assessed by comparing the F/E ratio between maternal and neonatal plasma (placental activity) and between plasma and urine in newborns (renal activity). Direct measurement of renal 11βHSD2 activity was subsequently evaluated in mice at various developmental stages. Renal 11βHSD2 mRNA and protein expression were analyzed by quantitative RT-PCR and immunohistochemistry during the perinatal period in both species.ResultsWe demonstrate that, at variance with placental 11βHSD2 activity, renal 11βHSD2 activity is weak in newborn human and mouse and correlates with low renal mRNA levels and absence of detectable 11βHSD2 protein.ConclusionsWe provide evidence for a weak or absent expression of neonatal renal 11βHSD2 that is conserved among species. This temporal and tissue-specific 11βHSD2 expression could represent a physiological window for glucocorticoid action yet may constitute an important predictive factor for adverse outcomes of glucocorticoid excess through fetal programming.
Highlights
Glucocorticoid hormones play a critical role in promoting maturation of fetal organs essential for neonatal adaptation to extrauterine terrestrial life
We have previously demonstrated that both mouse and human newborns have very low renal mineralocorticoid receptor (MR) expression at birth [28]
When we compared F/E ratio in both maternal and umbilical cord blood, we found a striking difference with a higher ratio in mothers than in newborns (5.260.30 vs 0.360.02, p,0.0001) in which E concentrations largely excedeed that of F (Fig. 1B). These results suggest that maternal cortisol is metabolized into cortisone by the placenta, afterwhich cortisone crosses the placental barrier into the fetal circulation
Summary
Glucocorticoid hormones play a critical role in promoting maturation of fetal organs essential for neonatal adaptation to extrauterine terrestrial life. Excessive glucocorticoid exposure in utero has numerous harmful effects It reduces fetal growth [4] and is associated with increased susceptibility to the development of hypertension [5,6,7], glucose intolerance [8] and anxiety related disorders in adulthood [9]. Excessive glucocorticoid exposure in utero can result in a variety of detrimental effects, such as growth retardation and increased susceptibility to the development of hypertension. Maternal glucocorticoids are metabolized into inactive compounds by placental 11beta-hydroxysteroid dehydrogenase type (11bHSD2). This enzyme is expressed in the kidney, where it prevents illicit occupation of the mineralocorticoid receptor by glucocorticoids. We investigated the role of renal 11bHSD2 in the control of neonatal glucocorticoid metabolism in the human and mouse
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