No abstract

It is well known that variation in the concentration of estrogens affects insulin action. In this study we examine the impact of estradiol (E2) on insulin signaling in the rat heart. Ovariectomized female rats were treated with E2 6 h prior to analysis of basal protein and mRNA content of insulin signaling molecules, and additionally with insulin 30 min before the experiment to delineate E2 effects on phosphorylations and molecular associations relevant for insulin signaling. The results show that E2 decreased insulin receptor (IR) tyrosine phosphorylation, while it did not alter IR protein and mRNA content. E2 administration did not change IR substrate 1 (IRS-1) protein content and tyrosine phosphorylation, while decreased mRNA content and increased its association with the p85 subunit of phosphatidylinositol 3-kinase (PI3K). E2 decreased protein and mRNA content of IR substrate 2 (IRS-2), while did not change IRS-2 tyrosine phosphorylation and IRS-2 association with p85. The increase of IRS-1/p85 is accompanied by increase of p85 protein and mRNA levels, and by stimulation of protein kinase B (Akt) Ser(473) phosphorylation. In contrast, Akt protein and mRNA content were not changed. In summary, although in some aspects cardiac insulin signaling is obviously improved by E2 treatment (increase of p85 mRNA and protein levels, enhancement of IRS-1/p85 association and Ser(473)Akt phosphorylation), the observed decrease of IR tyrosine phosphorylation, IRS-2 protein content, and IRSs mRNA contents, suggest very complex interplay of beneficial and suppressive effects of E2, both genomic and non-genomic, in regulation of heart insulin signaling.

No abstract

The glucocorticoid receptors in lymphocytes of patients treated with glucocorticoids after kidney transplantation have been studied in order to determine whether abnormalities in corticosteroid binding and trans-activation of steroid-receptor complexes, i.e., their translocation into nuclei, may contribute to the resistance of patients to glucocorticoid therapy. The patients were divided into two groups, according to graft stability: patients with stable graft function and those with chronic allograft rejection. The study revealed changes in both level and binding affinity of glucocorticoid receptors in peripheral blood lymphocytes from patients with chronic graft rejection, compared with control level, as well as with values of patients with stable graft function. These data indicate that sensitivity to glucocorticoids depends, at least in part, on the alterations of glucocorticoid receptors. The receptor translocation into nuclei indicates that unknown post-receptor events might also be involved in glucocorticoid resistance that seriously impair successive glucocorticoid therapy after organ transplantation. Further examination of glucocorticoid receptors in cases of organ transplantation seems warranted.

The responses of liver glucocorticoid receptor (GR) and genes coding for a glucocorticoid-inducible tyrosine aminotransferase (TAT) and two acute-phase proteins (APP) [α₂-macroglobulin (α₂-M) and γ-fibrinogen (Fb)] to changes in glucocorticoid (GC) and proinflammatory (AP) cytokine contents have been examined in rats after single or combined treatments with turpentine oil, dexamethasone (Dex) and adrenalectomy. Activation of two APP genes in turpentine-induced inflammation was accompanied by an increase in the level of GR mRNA and a preferential translocation of GR-GC complexes to the nucleoplasm, while the expression of TAT remained unaltered. Dex alone caused a decrease in the levels of GR and Fb mRNAs, activation of TAT and α₂-M genes, a decrease in the affinity of hormone binding sites and redistribution of translocated GR-Dex complexes within the nuclei. Inflammation potentiated the effect which Dex alone exerted on the GR content and the number of GR binding sites but counteracted its influence on the affinity of GR binding sites and nuclear distribution of GR-Dex complexes. Adrenalectomy promoted a fall in TAT mRNA, no changes in the GR and Fb mRNA, a decrease in the affinity of GR hormone binding sites and redistribution of GR-hormone complexes within the nuclei. The AP cytokines released in response to inflammation exerted a counteracting effect on the adrenalectomy-induced changes in the affinity of hormone binding sites and nuclear distribution of GR-hormone complexes. They potentiated a fall of TAT mRNA but promoted full expression of the Fb gene. These results argue strongly for the influence of AP cytokines on the functional state of the GR and GC signaling pathways.