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

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.

Segmental sodium reabsorption by the renal tubule in prenatally programmed hypertension in the rat

“…Renal glucocorticoid receptor expression [17] and the ratio of angiotensin II AT 1 /AT 2 receptors [29] are increased in LP rats. By standardizing the endocrine input to the kidney, we may have stimulated a greater response in the LP rats compared with control animals, which is a limitation of our approach.…”

“…In the LP model, NHE-3 and ENaC are unaltered but NKCC2 and, in some reports, NCC are increased [14][15][16]. One group also described increased renal Na + :K + adenosine triphosphatase (ATPase_-α 1 and-β 1 subunit messenger RNA (mRNA) expression in LP rat kidneys [17], whereas we have shown that whole-kidney Na + :K + ATPase pump activity and expression of the α 1 subunit in the inner medulla are reduced markedly [15]. Most attention has focussed on the increase in NKCC2 mRNA and protein expression in the TAL of the LP rat, as this might be expected to result in renal sodium retention and thus an increase in blood pressure.…”

Feeding pregnant rats a low-protein diet alters the hepatic expression of SREBP-1c in their offspring via a glucocorticoid-related mechanism

“…Previous work found that maternal protein restriction leads to down-regulation of 11b-hydroxysteroid dehydrogenase-2 in placenta and consequently, increased foetal exposure to maternal glucocorticoids [19,20,25,26]. This has been proposed to underlie the effects of low-protein diet on offspring phenotypes such as development of hypertension [20,23].…”

“…This has been proposed to underlie the effects of low-protein diet on offspring phenotypes such as development of hypertension [20,23]. Glucocorticoid excess has been linked to clinical observations associated with the metabolic syndrome such as central obesity, hypertension, hyperlipidaemia and glucose intolerance [27].…”

“…It is proposed that glucocorticoids of maternal origin play an important mechanistic role in this nutritional programming. Maternal low-protein feeding down-regulates the expression of 11b-hydroxysteroid dehydrogenase 2 in the rat placenta [19,20]. It is suggested that the resulting over-exposure of foetal tissues to maternal glucocorticoids may have a central role in long-term programming of gene expression [21].…”