Endocrine Research Laboratory, Aurora St. Luke's Medical Center, Advocate Aurora Research Institute, Milwaukee, WI 53215, USA.
Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Endocrinology. 2022 Jan 1;163(1). doi: 10.1210/endocr/bqab232.
Hypoxia, a common stressor with preterm birth, increases morbidity and mortality associated with prematurity. Glucocorticoids (GCs) are administered to the preterm infant to improve oxygenation; prolonged use of GCs remains controversial. We evaluated a selective glucocorticoid receptor (GR) antagonist (CORT113176) in our neonatal rat model of human prematurity to assess how fasting and hypoxia-induced increases in neonatal corticosterone affects endogenous hormones and endocrine pancreas function. Neonatal rat pups at postnatal day (PD) 2, PD8, and PD15 were pretreated with CORT113176 and, after 60 minutes of separation and fasting, exposed to hypoxia (8% O2) or control (normoxia) for 30 or 60 minutes while fasting was continued. Plasma corticosterone, ACTH, glucose, and insulin were measured and fasting Homeostatic Model Assessment of Insulin Resistance was calculated. Glucocorticoid and insulin receptor-sensitive gene mRNAs were analyzed in liver, muscle, and adipose to evaluate target tissue biomarkers. CORT113176 pretreatment augmented baseline and hypoxia-induced increases in corticosterone and attenuated hypoxia-induced increases in insulin resistance at PD2. Normoxic and hypoxic stress increased the hepatic GR-sensitive gene mRNAs, Gilz and Per1; this was eliminated by pretreatment with CORT113176. CORT113176 pretreatment decreased baseline insulin receptor-sensitive gene mRNAs Akt2, Irs1, Pik3r1, and Srebp1c at PD2. We show that CORT113176 variably augments the stress-induced increases in corticosterone concentrations (attenuation of negative feedback) and that GR is critical for hepatic responses to stress in the hypoxic neonate. We also propose that measurement of Gilz and Per1 mRNA expression may be useful to evaluate the effectiveness of GR antagonism.
缺氧是导致早产的常见应激源，会增加早产儿的发病率和死亡率。为了改善氧合，会给早产儿使用糖皮质激素（GCs）；但 GC 的长期使用仍存在争议。我们在早产的新生大鼠模型中评估了一种选择性糖皮质激素受体（GR）拮抗剂（CORT113176），以评估新生儿皮质酮在禁食和缺氧诱导下的增加如何影响内源性激素和内分泌胰腺功能。在出生后第 2、8 和 15 天（PD），对新生大鼠幼崽进行 CORT113176 预处理，在 60 分钟的分离和禁食后，将其暴露于缺氧（8% O2）或对照（常氧）中 30 或 60 分钟，同时继续禁食。测量血浆皮质酮、ACTH、葡萄糖和胰岛素，并计算禁食稳态模型评估的胰岛素抵抗。分析肝脏、肌肉和脂肪中的糖皮质激素和胰岛素受体敏感基因 mRNA，以评估靶组织生物标志物。CORT113176 预处理增强了 PD2 时基础和缺氧诱导的皮质酮增加，并减轻了缺氧诱导的胰岛素抵抗增加。常氧和缺氧应激增加了肝脏 GR 敏感基因 mRNAs Gilz 和 Per1；这被 CORT113176 预处理消除了。CORT113176 预处理降低了 PD2 时基础胰岛素受体敏感基因 mRNAs Akt2、Irs1、Pik3r1 和 Srebp1c 的表达。我们表明，CORT113176 可改变增强皮质酮浓度的应激诱导增加（负反馈减弱），并且 GR 对于新生儿在缺氧时的肝脏应激反应至关重要。我们还提出，测量 Gilz 和 Per1 mRNA 表达可能有助于评估 GR 拮抗作用的有效性。
