Restrained expression of canine glucocorticoid receptor splice variants α and P prognosticates fatal disease outcome in SIRS

Abstract

Glucocorticoids play a central role in the inflammatory response and alleviate the symptoms in critically ill patients. The glucocorticoid action relies on the glucocorticoid receptor (GR) which translocates into the nucleus upon ligand-binding and regulates transcription of a battery of genes. Although the GR is encoded by a single gene, dozens of its splice variants have been described in diverse species. The GRα isoform encodes the full, functionally active protein that is composed of a transactivation, a DNA-binding, and a C-terminal ligand-binding domain. The second most highly expressed receptor variant, the GR-P, is formed by an intron retention that introduces an early stop codon and results in a probably dysfunctional protein with truncated ligand-binding domain. We described the canine ortholog of GR-P and showed that this splice variant is highly abundant in the peripheral blood of dogs. The level of cGRα and cGR-P transcripts are elevated in patients of SIRS and the survival rate is increased with elevated cGRα and cGR-P expression. The ratio of cGRα and cGR-P mRNA did not differ between the survivor and non-survivor patients; thus, the total GR expression is more pertinent than the relative expression of GR isoforms in assessment of the disease outcome.