The maternal diet during pregnancy programs altered expression of the glucocorticoid receptor and type 2 11β-hydroxysteroid dehydrogenase:: Potential molecular mechanisms underlying the programming of hypertension in utero
The maternal diet during pregnancy programs altered expression of the glucocorticoid receptor and type 2 11β-hydroxysteroid dehydrogenase:: Potential molecular mechanisms underlying the programming of hypertension in utero
复制标题
DOI：
10.1210/en.142.7.2841
复制
发表时间：
2001-07-01
期刊：
影响因子：
4.8
通讯作者：
Whorwood, CB
中科院分区：
文献类型：
--
作者：
Bertram, C;Trowern, AR;Whorwood, CB
使用大鼠模型研究了成年期产前高血压编程的潜在机制，其中母体蛋白质摄入量限制在9%。18%酪蛋白（对照）在怀孕期间。母体低蛋白（MLP）后代表现出糖皮质激素依赖性收缩压升高，贯穿整个生命周期（高于对照20-30 mm Hg）。为了确定糖皮质激素作用改变在MLP后代高血压产前编程中作用的分子机制，分析组织中糖皮质激素受体（GR）、盐皮质激素受体（MR）、11 β HSD 1、11 β HSD 2和皮质类固醇反应性Na/K-腺苷三磷酸酶α 1和β 1。在胎儿和新生儿期，MLP后代的肾、肝、肺和脑中GR蛋白（95 kDa）和信使RNA（mRNA）的表达是对照后代的1倍多，在随后的幼年和成年期则是对照后代的3倍多（P < 0.01）。这与Na/K-腺苷三磷酸酶α 1-和β 1-亚基mRNA表达水平的增加有关。MR基因表达水平保持不变。暴露于MLP饮食也导致妊娠第14天和第20天MLP胎盘中11 β HSDB表达水平显著降低（P < 0.001），这支持了我们先前报道的对11 β HSD 2酶活性的类似影响。MLP子代在胎儿期和出生后肾脏和肾上腺中的水平也显著降低（P < 0.001）。11 β HSDB的这种程序性下降可能导致这些组织中糖皮质激素作用的显著增加，并增强GR和MR介导的血压升高诱导。相比之下，11 β HSD 1 mRNA的表达水平在后代的中央和外周tissues.In结论保持不变，我们已经证明，轻度蛋白质限制在怀孕期间的程序组织特异性增加糖皮质激素的作用，介导的持续升高的GR的表达和11 β HSDB的表达在成年后的生活。由于糖皮质激素不仅是胎儿生长的有效调节剂，而且也是血压的调节剂，我们的数据表明，重要的潜在分子机制有助于通过大鼠母体营养不良进行产前高血压编程。
Potential mechanisms underlying prenatal programming of hypertension in adult life were investigated using a rat model in which maternal protein intake was restricted to 9% us. 18% casein (control) during pregnancy. Maternal low protein (MLP) offspring exhibit glucocorticoid-dependent raised systolic blood pressure throughout life (20-30 mm Hg above the control).To determine the molecular mechanisms underlying the role of alterations in glucocorticoid hormone action in the prenatal programming of hypertension in MLP offspring, tissues were analyzed for expression of the glucocorticoid receptor (GR), mineralocorticoid receptor (MR), 11 beta HSD1, 11 beta HSD2, and corticosteroid-responsive Na/K-adenosine triphosphatase alpha1 and beta1. GR protein (95 kDa) and messenger RNA (mRNA) expression in kidney, liver, lung, and brain was more than a-fold greater in MLP vs. control offspring during fetal and neonatal life and was more than 3-fold higher during subsequent juvenile and adult life (P < 0.01). This was associated with increased levels of Na/K-adenosine triphosphatase alpha1- and beta1-subunit mRNA expression. Levels of MR gene expression remained unchanged. Exposure to the MLP diet also resulted in markedly reduced levels of 11 beta HSDB expression in the MLP placenta on days 14 and 20 of gestation (P < 0.001), underpinning similar effects on 11 beta HSD2 enzyme activity that we reported previously. Levels were also markedly reduced in the kidney and adrenal of MLP offspring during fetal and postnatal life (P < 0.001). This programmed decline in 11 beta HSDB probably contributes to marked increases in glucocorticoid hormone action in these tissues and potentiates both GR- and MR-mediated induction of raised blood pressure. In contrast, levels of 11 beta HSD1 mRNA expression in offspring central and peripheral tissues remained unchanged.In conclusion, we have demonstrated that mild protein restriction during pregnancy programs tissue-specific increases in glucocorticoid hormone action that are mediated by persistently elevated expression of GR and decreased expression of 11 beta HSDB during adult life. As glucocorticoids are potent regulators not only of fetal growth but also of blood pressure, our data suggest important potential molecular mechanisms contributing to the prenatal programming of hypertension by maternal undernutrition in the rat.