Evidence That Prenatal Programming of Hypertension by Dietary Protein Deprivation Is Mediated by Fetal Glucocorticoid Exposure

Abstract

Background Prenatal programming by maternal dietary protein deprivation and prenatal dexamethasone result in a reduction in nephron number and hypertension when the offspring are studied as adults. Methods To determine whether prenatal dietary protein deprivation results in a reduction in nephron number and hypertension in offspring by exposure to maternal glucocorticoids, we administered metyrapone to rats fed either a 6% or 20% protein diet to inhibit glucocorticoid production and compared the offspring to rats that were the product of mothers fed either a 6% or 20% protein diet during the last half of pregnancy. Results Male offspring from the 6% group had elevated systolic blood pressure (149 ± 2 vs. 130 ± 5 mm Hg, P < 0.05) and a reduction in glomeruli compared to the 20% group (22,111 ± 627 vs. 29,666 ± 654 glomeruli/kidney, P < 0.001). Maternal metyrapone administration did not affect the blood pressure in the 20% group but ameliorated the increase in blood pressure in the 6% male group to values comparable to the 20% control group (138 ± 6 vs. 130 ± 5 mm Hg). Male offspring of the 6% group that received metyrapone had an increase in the number of glomeruli compared to the vehicle-treated 6% group (26,780 ± 377 vs. 22,111 ± 627 glomeruli/kidney, P < 0.001), but less glomeruli compared to the 20% protein control group (26,780 ± 377 vs. 29,666 ± 654 glomeruli/kidney, P = 0.01). Conclusions The reduction in nephron number and hypertension induced by maternal protein deprivation in male offspring is ameliorated by inhibition of glucocorticoid production.

Prenatal glucocorticoid exposure programs adrenal PNMT expression and adult hypertension

“…Antenatal GC administration has previously been used experimentally to program offspring for adult hypertension , Levitt et al 1996, Ortiz et al 2002, O'Regan et al 2008, Habib & Gattineni 2011. In this study, we demonstrate that administration of the synthetic GC, DEX during the third trimester of gestation results in elevated systolic, diastolic, and mean arterial blood pressure in WKY male rats.…”

“…Further, studies have observed that exposure to high doses of glucocorticoids (GCs) during fetal development, generated either as a consequence of maternal stressors or administered antenatally also reduces birth weight and leads to development of essential hypertension later in life , Drake et al 2007. The role of GCs in the fetal programming of hypertension has been investigated in sheep (Dodic et al 2002), rats , Levitt et al 1996, Ortiz et al 2002, O'Regan et al 2008, Habib & Gattineni 2011, as well as in humans (Karemaker et al 2006). However, the exact mechanisms by which GC-mediated fetal programming of hypertension occurs requires further investigation.…”

Effect of prenatal programming and postnatal rearing on glomerular filtration rate in adult rats

“…Pregnant Sprague-Dawley rats were fed either a control 20% protein diet or a 6% (low) protein diet from the 12th day of gestation until the time of birth using the same protocol as previously described (9,13,14,25). The mothers had all been pregnant previously and were 4 -6 mo of age.…”

Metyrapone Blocks Maternal Food Restriction-Induced Changes in Female Rat Offspring Lung Development

“…This dosing regimen of MTP has been used effectively in many previous studies. 14,15 At day 1 after birth, the litters were separated by gender, and the body weights of individual pups were recorded. To avoid any undue bias toward selecting heavier or lighter pups, the median body weight per litter per gender was determined, and the 4 females closest to the median body weight for the litter were selected for the study; we chose to focus on only 1 gender (females), since there is a well-known gender effect on lung development.…”