Wyrwoll Caitlin S, Mark Peter J, Waddell Brendan J
School of Anatomy and Human Biology, University of Western Australia, Nedlands, Perth, Australia.
Hypertension. 2007 Sep;50(3):579-84. doi: 10.1161/HYPERTENSIONAHA.107.091603. Epub 2007 Jul 30.
Fetal glucocorticoid excess leads to subsequent adult hypertension, but the mechanisms involved in this developmental programming remain largely unknown. In this study we tested the hypothesis that programmed hypertension in rats is linked to altered renal expression of the glucocorticoid receptor, mineralocorticoid receptor, and 11beta-hydroxysteroid dehydrogenase type 2 and components of the intrarenal and adipose renin-angiotensin system. The interactive effects of a postnatal diet enriched in omega-3 fatty acids, which prevents emergence of the hypertensive phenotype, were also examined. Maternal dexamethasone (0.75 microg/mL of drinking water from day 13 to term) markedly increased renal expression of the glucocorticoid receptor in 6-month-old offspring, and this was associated with hypomethylation of the glucocorticoid receptor promoter; renal MR was unaffected. In contrast, maternal dexamethasone reduced renal 11beta-hydroxysteroid dehydrogenase type 2 in offspring, but this effect was prevented by a high omega-3 diet. Consistent with these effects, renal Na/K-ATPase-alpha1 was elevated in offspring of dexamethasone-treated mothers, but only in those raised on the standard diet. Maternal dexamethasone also programmed increased expression of renal and adipose angiotensin-converting enzyme and renal renin, but among these changes, only that of renal angiotensin-converting enzyme was prevented by the omega-3 diet. Our data support the hypothesis that programmed hypertension is mediated, in part, by increased renal glucocorticoid sensitivity, with consequent stimulatory effects on Na/K-ATPase-alpha1 and intrarenal renin-angiotensin system components. Partial prevention of programmed changes in renal gene expression by postnatal dietary omega-3 fatty acids provides insight into how this intervention prevents hypertension induced by fetal glucocorticoid excess.
胎儿期糖皮质激素过量会导致成年后高血压，但这种发育编程所涉及的机制在很大程度上仍不清楚。在本研究中，我们检验了这样一个假设，即大鼠的程序化高血压与糖皮质激素受体、盐皮质激素受体、2型11β-羟基类固醇脱氢酶以及肾内和脂肪肾素-血管紧张素系统成分的肾表达改变有关。我们还研究了富含ω-3脂肪酸的产后饮食（可预防高血压表型的出现）的交互作用。母体地塞米松（从第13天到足月，饮用水中含0.75μg/mL）显著增加了6个月大后代肾内糖皮质激素受体的表达，这与糖皮质激素受体启动子的低甲基化有关；肾内盐皮质激素受体未受影响。相反，母体地塞米松降低了后代肾内2型11β-羟基类固醇脱氢酶的水平，但高ω-3饮食可预防这种作用。与这些作用一致，地塞米松处理的母亲的后代肾内钠钾ATP酶-α1升高，但仅在那些以标准饮食喂养的后代中出现。母体地塞米松还使肾和脂肪组织中血管紧张素转换酶以及肾素的表达增加，但在这些变化中，只有肾血管紧张素转换酶的变化可被ω-3饮食预防。我们的数据支持这样一个假设，即程序化高血压部分是由肾糖皮质激素敏感性增加介导的，从而对钠钾ATP酶-α1和肾内肾素-血管紧张素系统成分产生刺激作用。产后饮食中的ω-3脂肪酸对肾基因表达程序化变化的部分预防作用，为这种干预措施预防胎儿期糖皮质激素过量所致高血压的机制提供了线索。
