Kalinyak J E, Griffin C A, Hamilton R W, Bradshaw J G, Perlman A J, Hoffman A R
Department of Medicine, Stanford University School of Medicine, California.
J Clin Invest. 1989 Dec;84(6):1843-8. doi: 10.1172/JCI114370.
The biological action of glucocorticoids is dependent upon tissue-specific levels of the glucocorticoid receptor (GR). During stress, the hypothalamic-pituitary-adrenal axis is stimulated, and high levels of glucocorticoids circulate. This axis is modulated by negative feedback by glucocorticoids, which inhibit hypothalamic and pituitary hormone secretion and downregulate GR gene expression. To study the developmental tissue-specific regulation of the GR, we measured the relative concentration of GR mRNA in fetal, neonatal, adult, and aged rats and examined the effects of dexamethasone on GR gene expression. Three different tissue-specific developmental patterns of GR mRNA accumulation were found. In addition, there was an age-dependent tissue-specific pattern in the feedback regulation of GR mRNA by glucocorticoids. In the fetus and neonate, GR mRNA abundance was not regulated by circulating glucocorticoids. The adult pattern of glucocorticoid feedback inhibition of GR mRNA expression appeared between 2 and 7 d of life in liver, and after 7 but before 14 d of age in brain. The GR was biologically active in the 2-d-old neonate, however, since dexamethasone enhanced gene expression of angiotensinogen, which is another glucocorticoid responsive gene. These data demonstrate that the GR gene is regulated by both developmental and tissue-specific factors, and provide another molecular basis for ontogenic variations in the hypothalamic-pituitary-adrenal response to stress.
糖皮质激素的生物学作用取决于糖皮质激素受体（GR）的组织特异性水平。在应激期间，下丘脑-垂体-肾上腺轴受到刺激，循环中糖皮质激素水平升高。该轴受到糖皮质激素的负反馈调节，糖皮质激素抑制下丘脑和垂体激素分泌并下调GR基因表达。为了研究GR的发育性组织特异性调节，我们测量了胎儿、新生儿、成年和老年大鼠中GR mRNA的相对浓度，并研究了地塞米松对GR基因表达的影响。发现了GR mRNA积累的三种不同的组织特异性发育模式。此外，糖皮质激素对GR mRNA的反馈调节存在年龄依赖性的组织特异性模式。在胎儿和新生儿中，GR mRNA丰度不受循环糖皮质激素的调节。糖皮质激素对GR mRNA表达的反馈抑制在成年期的模式在出生后2至7天出现在肝脏中，在出生后7天但在14天之前出现在大脑中。然而，GR在2日龄新生儿中具有生物学活性，因为地塞米松增强了血管紧张素原（另一种糖皮质激素反应性基因）的基因表达。这些数据表明，GR基因受发育和组织特异性因素的调节，并为下丘脑-垂体-肾上腺对应激反应的个体发生变化提供了另一个分子基础。
