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, 140.1W2.4 vs. 128.6W3.2mmHg; PU0.009), hypokalemic (4.5W0.2 vs. 5.1W0.2 mmol/l; PU0.03) and had suppressed plasma renin concentration (23.6W4.8 vs. 43.8W5.9 ng/ml; PU0.017). 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 (136.1W27.0 vs. 303.6W47.0 ng/kg; PU0.008). Accordingly, we assessed renal factors that might influence mineralocorticoid responsiveness. Renal expression of mineralocorticoid receptor and glucocorticoid receptor mRNAs was unaltered, as was 11b-hydroxysteroid dehydrogenase type 1 (11b-HSD1) which regenerates active glucocorticoids. However, renal mRNA for 11b-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 (Pconfirmedbymeasurements of renal11b-HSDactivityand 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.
Conclusion The blood pressure phenotype of DEXprogrammed rats may in part be explained by a life-long reduction in renal 11b-HSD2 activity. Salt-sensitive hypertension could be programmed by prenatal stress.
