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

Karen Moritz, Robert De Matteo, Miodrag Dodic, Andrew Jeffries, Debbie Arena, Marelyn Wintour-Coghlan, Megan Probyn, John Bertram, Reetu Singh, Simone Zanini, Roger Evans

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Abstract

Treatment of the pregnant ewe with glucocorticoids early in pregnancy results in offspring with hypertension. This study examined if 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 month old lambs whilst arterial pressure and renal function was examined in adult female offspring before and during 6 weeks of increased dietary salt intake. Pregnant ewes were treated with saline (SAL), dexamethasone (DEX-0.48mg/h) or cortisol (CORT-5mg/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 (alpha, beta, gamma subunits) and Na/K ATPase (alpha, beta, gamma subunits) in both the DEX and CORT groups compared to the SAL groupgroup with some of these changes persisting in 2 month old female offspring. In adulthood, sheep treated with DEX or CORT 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 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 CORT and DEX exposed sheep, since it would be expected to promote salt and water retention during the post-natal period.
Original languageEnglish
Pages (from-to)R500 - R509
Number of pages10
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume301
Issue number2
DOIs
Publication statusPublished - 2011

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