Developmental Programming of Renal Glucocorticoid Sensitivity and the Renin-Angiotensin System

Abstract

Abstract-Fetal glucocorticoid excess leads to subsequent adult hypertension, but the mechanisms involved in this developmental programming remain largely unknown. In this study we tested the hypothesis that programmed hypertension in rats is linked to altered renal expression of the glucocorticoid receptor, mineralocorticoid receptor, and 11␤-hydroxysteroid dehydrogenase type 2 and components of the intrarenal and adipose renin-angiotensin system. The interactive effects of a postnatal diet enriched in omega-3 fatty acids, which prevents emergence of the hypertensive phenotype, were also examined. Maternal dexamethasone (0.75 g/mL of drinking water from day 13 to term) markedly increased renal expression of the glucocorticoid receptor in 6-month-old offspring, and this was associated with hypomethylation of the glucocorticoid receptor promoter; renal MR was unaffected. In contrast, maternal dexamethasone reduced renal 11␤-hydroxysteroid dehydrogenase type 2 in offspring, but this effect was prevented by a high omega-3 diet. Consistent with these effects, renal Na/K-ATPase-␣1 was elevated in offspring of dexamethasone-treated mothers, but only in those raised on the standard diet. Maternal dexamethasone also programmed increased expression of renal and adipose angiotensin-converting enzyme and renal renin, but among these changes, only that of renal angiotensin-converting enzyme was prevented by the omega-3 diet. Our data support the hypothesis that programmed hypertension is mediated, in part, by increased renal glucocorticoid sensitivity, with consequent stimulatory effects on Na/K-ATPase-␣1 and intrarenal renin-angiotensin system components. Partial prevention of programmed changes in renal gene expression by postnatal dietary omega-3 fatty acids provides insight into how this intervention prevents hypertension induced by fetal glucocorticoid excess. Key Words: prenatal programming Ⅲ hypertension Ⅲ glucocorticoids Ⅲ 11␤-hydroxysteroid dehydrogenase type 2 Ⅲ renin-angiotensin system Ⅲ kidney Ⅲ omega-3 fatty acids D evelopmental programming is now recognized as a key determinant of the adult phenotype, most notably in relation to regulation of blood pressure, insulin sensitivity, and adiposity. 1 Thus, fetal insults, such as undernutrition or glucocorticoid excess, can lead to adult hypertension and insulin resistance, but the mechanisms underlying such programming outcomes remain largely unknown. 2,3 Moreover, the severity of the programmed phenotype can be either reduced or exacerbated by the postnatal environment. Specifically, adult hypertension programmed by fetal undernutrition is worsened by a hypercaloric diet in postnatal life, 4 whereas we recently reported that hypertension programmed by maternal dexamethasone treatment is prevented when offspring are raised on a diet enriched with omega-3 (n-3) fatty acids. 5 This rescue of the programmed phenotype is consistent with the well-recognized, beneficial effects of dietary n-3 fatty acids in relation to human hypertension. 6 Interestingly, hyperleptinemia ...

Expression discordance of monozygotic twins at birth: Effect of intrauterine environment and a possible mechanism for fetal programming

“…[2][3][4][5] Other studies in rodents and humans have shown that intrauterine environment can influence phenotype through its effect on epigenetic profile. [6][7][8][9] Rates of epigenetic fidelity through cell division are lower than those for genetic fidelity, with epimutation being one to Within-pair comparison of monozygotic (MZ) twins provides an ideal model for studying factors that regulate epigenetic profile, by controlling for genetic variation. Previous reports have demonstrated epigenetic variability within MZ pairs, but the contribution of early life exposures to this variation remains unclear.…”

Developmental programming of adult adrenal structure and steroidogenesis: effects of fetal glucocorticoid excess and postnatal dietary omega-3 fatty acids

“…In addition, we measured urinary levels of corticosterone and aldosterone and adrenal expression of key genes that promote adrenal steroidogenesis. The interactive effects of a postnatal, high-omega-3 fatty acid diet were also assessed because our previous studies show that this dietary intervention prevents several of the adverse phenotypic outcomes of maternal dexamethasone treatment (Wyrwoll et al 2006(Wyrwoll et al , 2007. It is not known, however, whether this beneficial effect of postnatal omega-3 fatty acid supplementation involves altered adrenal function.…”

Glucocorticoids: Biochemical Group That Play Key Role in Fetal Programming of Adult Disease

“…GCs-exposed offspring has decreased 11 β-HSD 2 expression and increased GR expression as well as GR promoter hypomethylation in kidney (189). Cortisol will then exert mineralocorticoid activity through MR binding in kidney and resulted in sodium and water retention, hypokalaemia, low plasma renin and aldosterone concentrations, and eventually hypertension in adult life (190).…”