Induction of the rat hepatic aryl hydrocarbon receptor nuclear translocator by glucocorticoids

Abstract

The aryl hydrocarbon receptor nuclear translocator (ARNT) is a shared partner between the hypoxia signaling pathway and the dioxin‐responsive aryl hydrocarbon receptor signaling pathway. Dexamethasone (DEX), a synthetic glucocorticoid known to activate both the glucocorticoid receptor (GR) and the pregnane X receptor (PXR), was shown previously to increase rat hepatic ARNT mRNA levels. To examine the roles of GR and PXR in this response, we treated male rats with the GR‐selective agonist triamcinolone acetonide (TA), the PXR‐selective agonist pregnenolone‐16α‐carbonitrile (PCN), and several doses of DEX. At 6 h following TA treatment, there was a 7.5‐fold induction of ARNT mRNA and a 4.5‐fold increase in levels of an unidentified lower molecular weight protein reacting with ARNT antibody. There was a trend for increased ARNT protein levels at 24 h after TA exposure. PCN treatment had no effect on these ARNT parameters. A low dose of DEX (1 mg/kg), shown to activate GR but not PXR, caused a 10‐fold induction of ARNT mRNA at 6 h along with a 6.5‐fold increase in levels of the unidentified ARNT antibody‐reactive protein. A trend for increased ARNT protein levels at 24 h was observed, but only at higher doses of DEX (10 to 50 mg/kg), shown to activate both GR and PXR. These findings suggest that the GR is a key mediator of the induction of rat hepatic ARNT expression by glucocorticoids. [Support: CIHR]