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Acute and Long-Term Effects of Clinical Doses of Antenatal Glucocorticoids in the Developing Fetal Sheep Kidney

Jie Zhang, MD

James C. Rose, PhD

Center for Research in Obstetrics and Gynecology, Department of Obstetrics and Gynecology, Wake Forest University School of Medicine, Winston-Salem, North Carolina

Jorge P. Figueroa, MD, PhD

Center for Research in Obstetrics and Gynecology, Department of Obstetrics and Gynecology, Wake Forest University School of Medicine, Winston-Salem, North Carolina; Department of Obstetrics and Gynecology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157; figueroa{at}wfubmc.edu

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 glucocrticoids 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 effectsof 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.

Key Words: Fetal programming • kidney cortex • antenatal steroids • AT2 receptor • fetal sheep

Journal of the Society for Gynecologic Investigation, Vol. 13, No. 3, 174-180 (2006)
DOI: 10.1016/j.jsgi.2006.01.005


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