Corticotroph isolation from Pomc-eGFP mice reveals sustained transcriptional dysregulation characterising a mouse model of glucocorticoid-induced suppression of the hypothalamus-pituitary-adrenal axis.
Corticotroph isolation from Pomc-eGFP mice reveals sustained transcriptional dysregulation characterising a mouse model of glucocorticoid-induced suppression of the hypothalamus-pituitary-adrenal axis.
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DOI：
10.1111/jne.13165
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发表时间：
2022-07
影响因子：
3.2
通讯作者：
Chambers, Thomas J. G.
中科院分区：
文献类型：
--
作者：
Duncan, Peter J.;McClafferty, Heather;Nolan, Oscar;Ding, Qinghui;Homer, Natalie Z. M.;Le Tissier, Paul;Walker, Brian R.;Shipston, Michael J.;Romano, Nicola;Chambers, Thomas J. G.
糖皮质激素(GC)的处方时间为3个月至英国人口的1%-3%；这些患者中有10%-50%出现下丘脑-垂体-肾上腺( )轴抑制，可能持续6个月以上，并与发病率和死亡率有关。恢复肾上腺功能需要恢复垂体和下丘脑的功能。我们建立了地塞米松(DEX)诱导的HPA轴功能障碍的小鼠模型，旨在进一步探索垂体的恢复。成年雄性野生型C57BL6/J或POMC-EGFP转基因小鼠随机分为地塞米松(约0.4g kg~(-1)体重 d-1)或口服地塞米松4 周，停药后0、1、4 周取材。用荧光激活细胞分选法从POMC-EGFP垂体中分离出促肾上腺皮质激素细胞，并提取RNA进行RNA测序。地塞米松治疗抑制了皮质酮的产生，皮质酮在地塞米松停药后至少一周仍受到部分抑制。停药后1周，肾上腺Hsd3b2、Cyp11a1和Mc2r基因表达显著降低，Mc2r和Cyp11a1基因表达持续降低。地塞米松治疗可使促肾上腺皮质激素转录组发生改变，停药后持续4 周的组间有一定差异。在停药后1周和4 周，地塞米松抑制的基因都没有表现出持续的衰减，而只有两个基因上调并在停药后保持不变。在抑制后增加的14个基因中，有14个基因在1周和4 周出现反弹，在被地塞米松抑制后增加的基因中，有6个基因在抑制后增加。慢性糖皮质激素治疗可能会导致脑垂体的持续性变化，这可能会影响未来对糖皮质激素治疗或应激的反应。
Glucocorticoids (GC) are prescribed for periods > 3 months to 1%–3% of the UK population; 10%–50% of these patients develop hypothalamus‐pituitary–adrenal (HPA) axis suppression, which may last over 6 months and is associated with morbidity and mortality. Recovery of the pituitary and hypothalamus is necessary for recovery of adrenal function. We developed a mouse model of dexamethasone (DEX)‐induced HPA axis dysfunction aiming to further explore recovery in the pituitary. Adult male wild‐type C57BL6/J or Pomc‐eGFP transgenic mice were randomly assigned to receive DEX (approximately 0.4 mg kg–1 bodyweight day–1) or vehicle via drinking water for 4 weeks following which treatment was withdrawn and tissues were harvested after another 0, 1, and 4 weeks. Corticotrophs were isolated from Pomc‐eGFP pituitaries using fluorescence‐activated cell sorting, and RNA extracted for RNA‐sequencing. DEX treatment suppressed corticosterone production, which remained partially suppressed at least 1 week following DEX withdrawal. In the adrenal, Hsd3b2, Cyp11a1, and Mc2r mRNA levels were significantly reduced at time 0, with Mc2r and Cyp11a1 remaining reduced 1 week following DEX withdrawal. The corticotroph transcriptome was modified by DEX treatment, with some differences between groups persisting 4 weeks following withdrawal. No genes supressed by DEX exhibited ongoing attenuation 1 and 4 weeks following withdrawal, whereas only two genes were upregulated and remained so following withdrawal. A pattern of rebound at 1 and 4 weeks was observed in 14 genes that increased following suppression, and in six genes that were reduced by DEX and then increased. Chronic GC treatment may induce persistent changes in the pituitary that may influence future response to GC treatment or stress.
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