Department of Anatomy and Developmental Biology, Monash University, Clayton, Australia.
Am J Physiol Regul Integr Comp Physiol. 2011 Aug;301(2):R500-9. doi: 10.1152/ajpregu.00818.2010. Epub 2011 May 18.
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.
孕期早期给怀孕母羊使用糖皮质激素会导致其后代出现高血压。本研究旨在探讨糖皮质激素是否会减少胎儿在妊娠晚期的肾单位形成或改变钠通道的基因表达。还检测了 2 月龄羔羊的钠通道表达情况，同时在成年雌性后代在增加盐摄入量的 6 周期间之前和期间检测了动脉血压和肾功能。妊娠母羊在妊娠第 26-28 天（足月= 150 天）分别接受生理盐水（SAL）、地塞米松（DEX；0.48mg/h）或皮质醇（CORT；5mg/h）治疗。在妊娠第 140 天，CORT 和 DEX 处理组的肾小球数量分别比 SAL 对照组少 40%和 25%。实时 PCR 显示，DEX 和 CORT 组胎儿肾脏中的上皮钠通道（α、β、γ 亚基）和 Na(+)-K(+)-ATP 酶（α、β、γ 亚基）的基因表达更高，其中一些变化在 2 月龄雌性后代中仍然存在。在成年期，子宫内接受地塞米松或皮质醇治疗的绵羊动脉血压升高，单个肾小球滤过率明显增加，但整体肾脏血液动力学和排泄功能正常，动脉血压对盐不敏感。我们的研究结果表明，在子宫内暴露于糖皮质激素的绵羊的肾单位缺陷是在出生前获得的，因此它是其成年期动脉血压升高的潜在原因，而不是结果。这些动物中钠通道的上调可能为皮质醇和地塞米松暴露的绵羊的动脉血压持续升高提供了一个机制联系，因为它预计会促进出生后盐和水的保留。
