The Maternal Diet during Pregnancy Programs Altered Expression of the Glucocorticoid Receptor and Type 2 11β-Hydroxysteroid Dehydrogenase: Potential Molecular Mechanisms Underlying the Programming of Hypertension in Utero*

Jun 21, 2001Endocrinology

How a mother's diet during pregnancy may change stress hormone regulation linked to developing high blood pressure before birth

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Abstract

Maternal low protein offspring exhibit 20-30 mm Hg raised systolic blood pressure throughout life compared to controls.

Increased glucocorticoid receptor (GR) expression was observed in kidney, liver, lung, and brain tissues of low protein offspring, being more than 2-fold greater during fetal and neonatal life and over 3-fold higher during juvenile and adult life.
Elevated expression of Na/K-adenosine triphosphatase alpha1- and beta1-subunit mRNA was associated with increased GR levels.
Maternal low protein diet led to significantly reduced levels of 11betaHSD2 expression in the placenta during gestation and in the kidney and adrenal glands during fetal and postnatal life.
The decline in 11betaHSD2 is likely linked to increased glucocorticoid hormone action in these tissues.
Consistent levels of 11betaHSD1 mRNA expression were found in central and peripheral tissues of offspring, indicating no impact from maternal low protein intake.

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Potential mechanisms underlying prenatal programming of hypertension in adult life were investigated using a rat model in which maternal protein intake was restricted to 9% vs. 18% casein (control) during pregnancy. Maternal low protein (MLP) offspring exhibit glucocorticoid-dependent raised systolic blood pressure throughout life (20-30 mm Hg above the control). To determine the molecular mechanisms underlying the role of alterations in glucocorticoid hormone action in the prenatal programming of hypertension in MLP offspring, tissues were analyzed for expression of the glucocorticoid receptor (GR), mineralocorticoid receptor (MR), 11betaHSD1, 11betaHSD2, and corticosteroid-responsive Na/K-adenosine triphosphatase alpha1 and beta1. GR protein (95 kDa) and messenger RNA (mRNA) expression in kidney, liver, lung, and brain was more than 2-fold greater in MLP vs. control offspring during fetal and neonatal life and was more than 3-fold higher during subsequent juvenile and adult life (P < 0.01). This was associated with increased levels of Na/K-adenosine triphosphatase alpha1- and beta1-subunit mRNA expression. Levels of MR gene expression remained unchanged. Exposure to the MLP diet also resulted in markedly reduced levels of 11betaHSD2 expression in the MLP placenta on days 14 and 20 of gestation (P < 0.001), underpinning similar effects on 11betaHSD2 enzyme activity that we reported previously. Levels were also markedly reduced in the kidney and adrenal of MLP offspring during fetal and postnatal life (P < 0.001). This programmed decline in 11betaHSD2 probably contributes to marked increases in glucocorticoid hormone action in these tissues and potentiates both GR- and MR-mediated induction of raised blood pressure. In contrast, levels of 11betaHSD1 mRNA expression in offspring central and peripheral tissues remained unchanged. In conclusion, we have demonstrated that mild protein restriction during pregnancy programs tissue-specific increases in glucocorticoid hormone action that are mediated by persistently elevated expression of GR and decreased expression of 11betaHSD2 during adult life. As glucocorticoids are potent regulators not only of fetal growth but also of blood pressure, our data suggest important potential molecular mechanisms contributing to the prenatal programming of hypertension by maternal undernutrition in the rat.

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The Maternal Diet during Pregnancy Programs Altered Expression of the Glucocorticoid Receptor and Type 2 11β-Hydroxysteroid Dehydrogenase: Potential Molecular Mechanisms Underlying the Programming of Hypertension in Utero*

Abstract

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