Tissue mRNA expression of the glucocorticoid receptor and its splice variants in fatal critical illness

P>Background Critical illness results in activation of the hypothalamic-pituitary-adrenal (HPA) axis, which might be accompanied by a peripheral adaptation in glucocorticoid sensitivity. Tissue sensitivity is determined by the active glucocorticoid receptor GR alpha, of which two splice variants involving the hormone-binding domain exist, GR beta and GR-P. Objective To study tissue mRNA expression of the GR and its splice variants in fatal critical illness. Design and methods We assessed mRNA expression of the GR alpha, GR beta and GR-P variants in liver (n = 58) and muscle (n = 65) of patients who had died after intensive care, and had been randomized for insulin treatment. We analysed whether GR mRNA expression was associated with insulin treatment, cortisol levels and glucocorticoid treatment. Results GR alpha and GR-P mRNA constituted 87 +/- 8% and 13 +/- 2%, respectively, of total GR mRNA in liver. GR beta mRNA could only be amplified in five liver samples. All variants were present in most muscle samples (alpha = 96 +/- 11%, P = 3 center dot 9 +/- 0 center dot 4%, beta = 0 center dot 010 +/- 0 center dot 002%). GR expression was not associated with insulin therapy. A strong positive relationship was observed between the different GR variants in both liver and muscle (P < 0 center dot 001 for all). Serum cortisol levels were negatively associated with liver GR alpha and muscle GR-P expression (P < 0 center dot 05). mRNA expression of both liver GR alpha and GR-P, but not muscle GR, was substantially lower in patients who had received exogenous glucocorticoids (P < 0 center dot 01). Conclusion We demonstrate the presence of GR alpha and GR-P mRNA in liver and of GR alpha, GR beta and GR-P mRNA in muscle, with no evidence for altered splicing in critical illness. In contrast to muscle GR, liver GR expression was substantially lower in patients receiving exogenous glucocorticoids.