Prenatal glucocorticoid exposure in the sheep alters renal development in utero: implications for adult renal function and blood pressure control

• Published in: American journal of physiology. Regulatory, integrative and comparative physiology integrative and comparative physiology, 2011-08, Vol.301 (2), p.R500-R509
• Main Authors: Moritz, Karen M, De Matteo, Robert, Dodic, Miodrag, Jefferies, Andrew J, Arena, Debbie, Wintour, E Marelyn, Probyn, Megan E, Bertram, John F, Singh, Reetu R, Zanini, Simone, Evans, Roger G
• Format: Article
• Language: English
• Subjects: Animals; Blood Glucose; Blood Pressure - drug effects; Dexamethasone - administration & dosage; Dexamethasone - toxicity; Drinking; Female; Gene expression; Gene Expression Regulation, Developmental - drug effects; Hydrocortisone - administration & dosage; Hydrocortisone - toxicity; Hypertension; Kidney - drug effects; Kidney - embryology; Kidneys; Male; Medical treatment; Pregnancy; Prenatal Exposure Delayed Effects; Sheep; Sheep - embryology; Sheep - urine; Sodium; Water - metabolism
• ISSN: 0363-6119; 1522-1490
• DOI: 10.1152/ajpregu.00818.2010

Treatment of the pregnant ewe with glucocorticoids early in pregnancy results in offspring with hypertension. This study examined whether glucocorticoids can reduce nephron formation or alter gene expression for sodium channels in the late gestation fetus. Sodium channel expression was also examined in 2-mo-old lambs, while arterial pressure and renal function was examined in adult female offspring before and during 6 wk of increased dietary salt intake. Pregnant ewes were treated with saline (SAL), dexamethasone (DEX; 0.48 mg/h) or cortisol (CORT; 5 mg/h) over days 26-28 of gestation (term = 150 days). At 140 days of gestation, glomerular number in CORT and DEX animals was 40 and 25% less, respectively, compared with SAL controls. Real-time PCR showed greater gene expression for the epithelial sodium channel (α-, β-, γ-subunits) and Na(+)-K(+)-ATPase (α-, β-, γ-subunits) in both the DEX and CORT group fetal kidneys compared with the SAL group with some of these changes persisting in 2-mo-old female offspring. In adulthood, sheep treated with dexamethasone or cortisol in utero had elevated arterial pressure and an apparent increase in single nephron glomerular filtration rate, but global renal hemodynamics and excretory function were normal and arterial pressure was not salt sensitive. Our findings show that the nephron-deficit in sheep exposed to glucocorticoids in utero is acquired before birth, so it is a potential cause, rather than a consequence, of their elevated arterial pressure in adulthood. Upregulation of sodium channels in these animals could provide a mechanistic link to sustained increases in arterial pressure in cortisol- and dexamethasone-exposed sheep, since it would be expected to promote salt and water retention during the postnatal period.