Developmental programming of renal glucocorticoid sensitivity and the renin-angiotensin system.
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 11beta-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 microg/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 11beta-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-alpha1 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-alpha1 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.
School of Anatomy and Human Biology, University of Western Australia, Nedlands, Perth, Australia.
Caitlin S
CS
Wyrwoll
Peter J
PJ
Mark
Brendan J
BJ
Waddell
D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000235:genetics / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D019175:DNA Methylation; D003907:Dexamethasone / Q000494:pharmacology; D004351:Drug Resistance; D005260:Female; D047109:Fetal Development / Q000502:physiology*; D005938:Glucocorticoids / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D007703:Peptidyl-Dipeptidase A / Q000235:genetics; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000378:metabolism; D012083:Renin / Q000235:genetics; D012084:Renin-Angiotensin System / Q000502:physiology*; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism
D005938:Glucocorticoids; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D003907:Dexamethasone; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D007703:Peptidyl-Dipeptidase A; D012083:Renin; C499075:Atp1a1 protein, rat; D000254:Sodium-Potassium-Exchanging ATPase