Acute and long-term effects of clinical doses of antenatal glucocorticoids in the developing fetal sheep kidney.

Abstract

Objectives: The controversy regarding potential long-term side effects of antenatal steroid administration for accelerating fetal lung maturation is still unresolved despite more than 30 years of experience. Studies in animals have demonstrated that administration of glucocorticoids during pregnancy alters renal expression of several key regulatory molecules at different developmental stages followed in most cases with the development of hypertension in the adult. We studied the effects of betamethasone on the expression of (1) NA,K-ATPAse pump; (2) the Na/H exchanger 3 (NAHE3); (3) angiotensin receptor (AT1 and AT2); and (4) the type 1 dopamine receptor (D1R).

Methods: Pregnant sheep were treated with either 0.17 mg/kg betamethasone or vehicle 24 hours apart at 80 and 81 days' gestation. Fetal kidneys were harvested at 81 and 135 days' gestation. Protein and mRNA levels were measured in kidney cortex.

Results: Betamethasone had acute and long-term effects on fetal kidney cortex gene expression. Acutely, mRNA abundance for AT2 was significantly lower and that of NHE3 significantly higher than in controls (0.4 +/- 0.02 vs 0.7 +/- 0.05; 1.2 +/- 0.16 vs 0.4 +/- 0.04; P < .05). At 135 days' gestation, AT2 receptor abundance remained lower than control (0.2 +/- 0.02 vs 0.4 +/- 0.02; P < .05), whereas D1R expression was higher (0.8 +/- 0.17 vs 0.5 +/- 0.06; P < .05). No changes in Na,K-ATPase of AT1 receptor at either of the two time points studied were observed. Antenatal steroid administration was not associated with premature labor or a reduction in either body weight or kidney weight.

Conclusion: Our findings strongly suggest that antenatal glucocorticoid administration according to National Institutes of Health (NIH) consensus guidelines may alter human fetal renal development. Further studies are needed to establish a direct relationship between alterations in fetal renal gene expression and the development of hypertension in adulthood.