Prenatal overexposure to glucocorticoids programs renal 11β-hydroxysteroid dehydrogenase type 2 expression and salt-sensitive hypertension in the rat.
OBJECTIVE
Prenatal glucocorticoid excess programs hypertension in adulthood. The underlying mechanisms are unknown. Here, we tested whether hypertension in this model is due to increased renal mineralocorticoid activity.


METHODS
Pregnant rats were injected daily with the synthetic glucocorticoid dexamethasone (DEX) or vehicle during the last week of pregnancy. Blood pressure, electrolytes and target gene expression were measured in the offspring.


RESULTS
Adult DEX-treated offspring were hypertensive (SBP, 140.1 ± 2.4 vs. 128.6 ± 3.2 mmHg; P = 0.009), hypokalemic (4.5 ± 0.2 vs. 5.1 ± 0.2 mmol/l; P = 0.03) and had suppressed plasma renin concentration (23.6 ± 4.8 vs. 43.8 ± 5.9 ng/ml; P = 0.017). DEX programming had similar effects in younger rats (age 2 months), but only when fed a high-salt diet. Although these data are consistent with excess mineralocorticoid activity, plasma aldosterone levels were unaffected and daily urinary aldosterone values were decreased (136.1 ± 27.0 vs. 303.6 ± 47.0 ng/kg; P = 0.008). Accordingly, we assessed renal factors that might influence mineralocorticoid responsiveness. Renal expression of mineralocorticoid receptor and glucocorticoid receptor mRNAs was unaltered, as was 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) which regenerates active glucocorticoids. However, renal mRNA for 11β-HSD2, which catalyses inactivation of glucocorticoids in the distal nephron and thus protects mineralocorticoids from glucocorticoids, was decreased by 45% in both new born and adult rats (P < 0.01). The functional significance of this reduction was confirmed by measurements of renal 11β-HSD activity and by demonstrating that the mineralocorticoid properties of cortisol were enhanced in DEX-programmed rats. Additionally, the difference in blood pressure between DEX and control groups was abolished upon administration of spironolactone, a mineralocorticoid receptor antagonist.


CONCLUSIONS
The blood pressure phenotype of DEX-programmed rats may in part be explained by a life-long reduction in renal 11β-HSD2 activity. Salt-sensitive hypertension could be programmed by prenatal stress.
Endocrinology Unit, Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, Scotland, UK.
Justin I
JI
Tang
Chris J
CJ
Kenyon
Jonathan R
JR
Seckl
Moffat J
MJ
Nyirenda
D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000235:genetics* / Q000378:metabolism*; D000450:Aldosterone / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001794:Blood Pressure / Q000187:drug effects; D003907:Dexamethasone / Q000008:administration & dosage / Q000633:toxicity*; D004573:Electrolytes / Q000097:blood; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005938:Glucocorticoids / Q000633:toxicity*; D006854:Hydrocortisone / Q000494:pharmacology; D006973:Hypertension / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology* / Q000503:physiopathology; D008901:Mineralocorticoids / Q000378:metabolism; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000201:enzymology / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011965:Receptors, Glucocorticoid / Q000235:genetics; D018161:Receptors, Mineralocorticoid / Q000235:genetics; D012083:Renin / Q000097:blood; D017673:Sodium Chloride, Dietary / Q000008:administration & dosage; D013312:Stress, Physiological
D004573:Electrolytes; D005938:Glucocorticoids; D008901:Mineralocorticoids; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D017673:Sodium Chloride, Dietary; D000450:Aldosterone; D003907:Dexamethasone; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D012083:Renin; D006854:Hydrocortisone