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The maternal diet during pregnancy programs altered expression of the glucocorticoid receptor and type 2 11ß-hydroxysteroid dehydrogenase: potential molecular mechanisms underlying the programming of hypertension in utero

The maternal diet during pregnancy programs altered expression of the glucocorticoid receptor and type 2 11ß-hydroxysteroid dehydrogenase: potential molecular mechanisms underlying the programming of hypertension in utero
The maternal diet during pregnancy programs altered expression of the glucocorticoid receptor and type 2 11ß-hydroxysteroid dehydrogenase: potential molecular mechanisms underlying the programming of hypertension in utero
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.
0013-7227
2841-2853
Bertram, C.E.
c23a6d53-1f31-4ade-992b-6f7598353873
Trowern, A.R.
69019c09-2cc8-421e-aeaa-be8c1846a3f2
Copin, N.
68395a46-55ea-42f7-9443-a3fd82558069
Jackson, A.A.
c9a12d7c-b4d6-4c92-820e-890a688379ef
Whorwood, C.B.
d944fa27-eaab-4180-b0ea-ebfb87f29f55
Bertram, C.E.
c23a6d53-1f31-4ade-992b-6f7598353873
Trowern, A.R.
69019c09-2cc8-421e-aeaa-be8c1846a3f2
Copin, N.
68395a46-55ea-42f7-9443-a3fd82558069
Jackson, A.A.
c9a12d7c-b4d6-4c92-820e-890a688379ef
Whorwood, C.B.
d944fa27-eaab-4180-b0ea-ebfb87f29f55

Bertram, C.E., Trowern, A.R., Copin, N., Jackson, A.A. and Whorwood, C.B. (2001) The maternal diet during pregnancy programs altered expression of the glucocorticoid receptor and type 2 11ß-hydroxysteroid dehydrogenase: potential molecular mechanisms underlying the programming of hypertension in utero. Endocrinology, 142 (7), 2841-2853.

Record type: Article

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), 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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Published date: 2001

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Local EPrints ID: 25250
URI: http://eprints.soton.ac.uk/id/eprint/25250
ISSN: 0013-7227
PURE UUID: 4f284151-ec67-408e-b406-6ec9663cf180

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Date deposited: 10 Apr 2006
Last modified: 22 Jul 2022 20:30

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Contributors

Author: C.E. Bertram
Author: A.R. Trowern
Author: N. Copin
Author: A.A. Jackson
Author: C.B. Whorwood

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