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Maternal low-protein diet in rat pregnancy programs blood pressure through sex-specific mechanisms
Sarah McMullen1, Simon C Langley-Evans
1Centre for Reproduction and Early Life, Division of Nutritional Biochemistry, University of Nottingham, Sutton Bonington Campus, Loughborough LE12 5RD, UK.
Insights
Maternal low-protein diet programs offspring hypertension, linked to glucocorticoids in males and AT2 receptor changes in females, suggesting sex-specific programming mechanisms.
Area of Science:
- Developmental programming
- Endocrinology
- Renal physiology
Background:
- Impaired fetal growth is linked to adult hypertension risk.
- Maternal nutrition and fetal glucocorticoid exposure can program offspring blood pressure.
- Angiotensin receptor (ATR) expression may be involved in this programming.
Purpose of the Study:
- To investigate the role of glucocorticoids and ATR expression in maternal low-protein diet-induced hypertension.
- To determine sex-specific effects of nutritional programming on blood pressure and renal ATR mRNA expression.
Main Methods:
- Wistar rats were fed a control or low-protein diet during pregnancy.
- Glucocorticoid dependency was assessed using metyrapone (corticosterone synthesis inhibitor).
- Offspring systolic blood pressure and renal AT(1)R and AT(2)R mRNA expression were measured at 4 weeks.
Main Results:
- Maternal low-protein diet increased systolic blood pressure in offspring, dependent on glucocorticoids in males only.
- AT(1)R mRNA expression was unaffected by diet or glucocorticoids.
- AT(2)R mRNA expression was downregulated in females, independent of glucocorticoids, and associated with hypertension.
Conclusions:
- Nutritional programming of hypertension involves sex-specific mechanisms.
- Glucocorticoids contribute to hypertension in male offspring, while AT(2)R downregulation is implicated in female offspring hypertension.
- The study does not support a direct interaction between glucocorticoids and ATR mRNA in this programming model.
Abstract:
Animal models support human epidemiological studies in demonstrating a relationship between impaired fetal growth and risk of adult hypertension. Undernutrition during pregnancy exerts programming effects on the developing kidney, and modulation of angiotensin receptor (ATR) expression has been observed persisting into adult life. Fetal overexposure to glucocorticoids is thought to be central to the nutritional programming of blood pressure and may act through an interaction with ATR expression. Pregnant female Wistar rats were fed a control (n = 6) or a maternal low-protein diet (MLP; n = 17) throughout pregnancy. The glucocorticoid dependency of MLP effects was tested using metyrapone, an inhibitor of corticosterone synthesis. MLP-fed rats were injected twice daily with metyrapone, metyrapone plus corticosterone, or vehicle over days 1-14 of pregnancy. At delivery, all animals were fed standard laboratory chow. MLP-exposed offspring 4 wk of age exhibited increased systolic blood pressure compared with controls (P < 0.05), which proved to be glucocorticoid dependent in males only. AT(1)R mRNA expression was independent of in utero dietary treatment. AT(2)R mRNA expression was downregulated in MLP-exposed females only (P < 0.05) and in a glucocorticoid-independent manner. Male offspring exhibited glucocorticoid-dependent hypertension with no modulation of renal ATR mRNA expression. In contrast, female offspring exhibited glucocorticoid-independent hypertension associated with reduced expression of renal AT(2)R mRNA. These data do not support the hypothesis that an interaction between glucocorticoid and ATR mRNA expression underlies the nutritional programming of blood pressure but instead suggest two independent mechanisms acting in a sex-specific manner.
