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

Abstract

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.