Modulation of hepatic and renal glucocorticoid receptors during aging of mice.

Abstract

The regulation of hepatic and renal glucocorticoid receptors (GRs) in young (4 weeks) and senescent (120 weeks) mice was studied. Significant changes in the level of GRs from liver and kidney were detected, whereas the affinity (Kd) for the hormone [3H]dexamethasone did not change in young and old mice. The concentration of GRs was markedly decreased in liver (25%) and kidney (33%) of old mice as compared to young ones. The magnitude of heat activation of GR complexes was more pronounced in both the tissues at young age compared to old. In addition, we have found changes in the heat activation-inhibition studies of GRs, using polyunsaturated fatty acids (PUFAs) as measured by binding to DNA-cellulose and purified nuclei. Linoleic acid (C18:2) exhibited significant decrease in heat activation of both hepatic and renal hormone-bound GR, with higher magnitude of inhibition in young liver (64%) and kidney (68%) as compared to old (41% and 43%, respectively). Arachidonic acid (C20:4) was also found to be an inhibitor of activation causing significant decrease in hepatic GR activation, with greater inhibition in young liver with respect to old, however, without any such difference in the kidney of young and old mice. Furthermore, DNase I digestion and extraction of nuclear-bound GR-complexes from both the tissues reveal lesser extraction in old liver (26%) and kidney (24%) compared to young tissues, indicating chromatin condensation with aging, thereby controlling the accessibility to such transcription factors as GRs. These findings indicate that the changes in the GR concentration, activation-modulation by PUFAs and chromatin organization, that take place during aging, may contribute to functional changes in glucocorticoid action mechanisms in senescent animals.