Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands.
Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.
J Endocrinol. 2020 Jul;246(1):79-92. doi: 10.1530/JOE-19-0486.
Glucocorticoids mediate numerous essential processes in the human body via binding to the glucocorticoid receptor (GR). Excessive GR signaling can cause disease, and GR antagonists can be used to treat many symptoms of glucocorticoid-induced pathology. The purpose of this study was to characterize the tissue-specific properties of the selective GR antagonist CORT125281. We evaluated the antagonistic effects of CORT125281 upon acute and subchronic corticosterone exposure in mice. In the acute corticosterone setting, hypothalamus-pituitary-adrenal-axis activity was investigated by measurement of basal- and stress-induced corticosterone levels, adrenocorticotropic hormone levels and pituitary proopiomelanocortin expression. GR signaling was evaluated by RT-PCR analysis of GR-responsive transcripts in liver, muscle, brown adipose tissue (BAT), white adipose tissue (WAT) and hippocampus. Pretreatment with a high dose of CORT125281 antagonized GR activity in a tissue-dependent manner. We observed complete inhibition of GR-induced target gene expression in the liver, partial blockade in muscle and BAT and no antagonism in WAT and hippocampus. Tissue distribution only partially explained the lack of effective antagonism. CORT125281 treatment did not disinhibit the hypothalamus-pituitary-adrenal neuroendocrine axis. In the subchronic corticosterone setting, CORT125281 partially prevented corticosterone-induced hyperinsulinemia, but not hyperlipidemia and immune suppression. In conclusion, CORT125281 antagonizes GR transcriptional activity in a tissue-dependent manner and improves corticosterone-induced hyperinsulinemia. Tailored dosing of CORT125281 may allow tissue-specific inhibition of GR transcriptional activity.
糖皮质激素通过与糖皮质激素受体（GR）结合来介导人体内许多重要的过程。过量的 GR 信号会导致疾病，而 GR 拮抗剂可用于治疗许多糖皮质激素诱导的病理症状。本研究的目的是描述选择性 GR 拮抗剂 CORT125281 的组织特异性特性。我们评估了 CORT125281 在急性和亚慢性皮质酮暴露下对小鼠的拮抗作用。在急性皮质酮环境中，通过测量基础和应激诱导的皮质酮水平、促肾上腺皮质激素水平和垂体前阿黑皮素原表达来研究下丘脑-垂体-肾上腺轴活性。通过 RT-PCR 分析肝脏、肌肉、棕色脂肪组织（BAT）、白色脂肪组织（WAT）和海马中 GR 反应性转录本来评估 GR 信号。高剂量的 CORT125281 预处理以组织依赖的方式拮抗 GR 活性。我们观察到 CORT125281 在肝脏中完全抑制 GR 诱导的靶基因表达，在肌肉和 BAT 中部分阻断，在 WAT 和海马中没有拮抗作用。组织分布仅部分解释了缺乏有效拮抗作用的原因。CORT125281 处理不会解除下丘脑-垂体-肾上腺神经内分泌轴的抑制。在亚慢性皮质酮环境中，CORT125281 部分预防了皮质酮诱导的高胰岛素血症，但不能预防高血脂和免疫抑制。总之，CORT125281 以组织依赖的方式拮抗 GR 转录活性，并改善皮质酮诱导的高胰岛素血症。CORT125281 的靶向给药可能允许组织特异性抑制 GR 转录活性。
