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Endocrinology and Metabolism Unit and Institute of Human Nutrition (A.A.J.), Division of the Fetal Origins of Adult Disease, School of Medicine, Southampton General Hospital, Southampton, United Kingdom SO16 6YD
Address all correspondence and requests for reprints to: Dr. Caroline Bertram, Centre for FOAD, Mailpoint 887, Princess Anne Hospital, Coxford Road, Southampton, United Kingdom SO16 5YD. E-mail: c.bertram{at}soton.ac.uk
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), 11ßHSD1, 11ßHSD2, and corticosteroid-responsive
Na/K-adenosine triphosphatase 
1 and ß1. 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 1- and ß1-subunit mRNA expression. Levels of MR
gene expression remained unchanged. Exposure to the MLP diet also
resulted in markedly reduced levels of 11ßHSD2 expression in the MLP
placenta on days 14 and 20 of gestation (P <
0.001), underpinning similar effects on 11ßHSD2 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 11ßHSD2
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 11ßHSD1
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 11ßHSD2 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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