FK-506 and rapamycin but not cyclosporin inhibit aldosterone-stimulated sodium transport in A6 cells

The immunosuppressants cyclosporin A (CyA), FK-506, and rapamycin (RAP) have multiple actions on target cells that appear to be mediated by interaction of drug-binding protein complexes. Both FK-506 and CyA, but not RAP, inhibit the Ca2+-dependent phosphatase, calcineurin, and in so doing have been found to inhibit Na+-K+-ATPase activity in various nephron segments. Of interest, FK-506 and RAP, but not CyA, are bound by the steroid receptor associated FK-506-binding heat shock protein of 56 kDa, HSP56. To determine the physiological effect of this interaction on a steroid-mediated phenomenon, the effect of these agents on steroid-mediated Na+ transport in A6 cells was investigated. Aldosterone stimulation of Na+ transport and Na+-K+-ATPase activity are significantly inhibited by prolonged incubation with FK-506 and RAP. Although CyA inhibits basal Na+-K+-ATPase activity, it has no effect on aldosterone-induced Na+ transport or the aldosterone-induced increase in Na+-K+-ATPase activity. FK-506 inhibits the aldosterone-induced synthesis of G alpha(i-3) protein but has no effect on glucocorticoid receptor number as quantified by Western blotting. The results suggest that FK-506 and RAP inhibit steroid-mediated Na+ transport at some pretranslational site. The common interaction of these agents with the steroid receptor-associated HSP56 might account for these findings.