Faculty Collaboration Database

Glucocorticoid Receptor Antagonist Alters Corticosterone and Receptor-sensitive mRNAs in the Hypoxic Neonatal Rat. Endocrinology 2022 Jan 01;163(1)

Date

11/19/2021

Pubmed ID

34791109

DOI

10.1210/endocr/bqab232

Scopus ID

2-s2.0-85122710601 (requires institutional sign-in at Scopus site)   3 Citations

Abstract

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.

Author List

Gehrand AL, Phillips J, Welhouse KD, Siddiqui H, Schulgit M, Hoffman J, Hunt H, Raff H

Author

Hershel Raff PhD Professor in the Academic Affairs department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adipose Tissue
Adrenal Cortex Hormones
Animals
Animals, Newborn
Female
Glucose
Hormones
Hypoxia
Insulin
Insulin Resistance
Isoquinolines
Liver
Male
Muscles
Pregnancy
Pregnancy, Animal
Premature Birth
Pyrazoles
RNA, Messenger
Rats
Rats, Sprague-Dawley
Receptors, Glucocorticoid
Receptors, Steroid