Endocrine Abstracts

Numerous epidemiological studies worldwide have shown a strong association between low birth weight and an increased risk of developing cardiometabolic disease, including hypertension. Excessive fetal exposure to glucocorticoids has been hypothesised to mediate this relationship. Here, we have used an established rodent model – in which dexamethasone, a synthetic glucocorticoid that readily crosses the placenta, is administered to pregnant Wistar rats during the last trimester – to investigate the molecular basis for the ‘programming’ of hypertension. In accord with previous observations, prenatal dexamethasone treatment reduced birth weight and elevated blood pressure in the adult (9 months old) male offspring. Intriguingly, the increase in blood pressure was accompanied by mild hypokalemia (5.09±0.18 vs 4.52±0.17 mM, P<0.05), suggesting an increase in renal mineralocorticoid activity. However, there were no significant differences in plasma aldosterone concentration or renal mineralocorticoid receptor (MR) mRNA expression between animals that were exposed to dexamethasone in utero and controls. In contrast, dexamethasone exposure was associated with a significant reduction in renal expression of 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) mRNA (43%, P<0.05), the pre-receptor barrier which protects MR from ‘illicit’ occupation by glucocorticoids by breaking down active glucocorticoids into inert compounds. Indeed, exogenous cortisol administration induced a fall in urinary sodium/potassium ratio in animals treated with dexamethasone in utero (0.31±0.03 vs 0.22±0.02, P<0.02), but not in controls, implying that cortisol might be acting as a mineralocorticoid when the 11β-HSD2 barrier is thus attenuated. The decrease in renal 11β-HSD2 mRNA expression was observed in animals as young as one week old. In summary, prenatal dexamethasone programmed a permanent decrease in renal 11β-HSD2 mRNA expression associated with physiological/metabolic derangements, mimicking a mild form of the syndrome of apparent mineralocorticoid excess. These data suggest that 11β-HSD2 plays a key role in the pathogenesis of hypertension following in utero overexposure to glucocorticoids.