Modulation of hepatic and renal glucocorticoid receptors during aging of mice

The regulation of hepatic and renal glucocorticoid receptors (GRs) in young(4 weeks) and senescent (120 weeks) mice was studied. Significant changesin the level of GRs from liver and kidney were detected, whereas theaffinity (Kd) for the hormone [3H]dexamethasone did notchange in young and old mice. The concentration of GRs was markedlydecreased in liver (25%) and kidney (33%) of old mice as compared toyoung ones. The magnitude of heat activation of GR complexes was morepronounced 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 toDNA-cellulose and purified nuclei. Linoleic acid (C18:2) exhibited significantdecrease 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 decreasein hepatic GR activation, with greater inhibition in young liver with respectto old, however, without any such difference in the kidney of young and oldmice. Furthermore, DNase I digestion and extraction of nuclear-boundGR-complexes from both the tissues reveal lesser extraction in old liver (26%)and kidney (24%) compared to young tissues, indicating chromatincondensation with aging, thereby controlling the accessibility to suchtranscription factors as GRs. These findings indicate that the changes inthe GR concentration, activation-modulation by PUFAs and chromatinorganization, that take place during aging, may contribute to functionalchanges in glucocorticoid action mechanisms in senescent animals.