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.
Rokaw
M D
MD
Laboratory of Epithelial Cell Biology, University of Pittsburg Medical Center, Pennsylvania, USA.
West
M E
ME
Palevsky
P M
PM
Johnson
J P
JP
D000450:Aldosterone / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line / Q000187:drug effects / Q000502:physiology; D016572:Cyclosporine / Q000494:pharmacology*; D004553:Electric Conductivity; D007166:Immunosuppressive Agents / Q000494:pharmacology; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology*; D009761:Nystatin / Q000494:pharmacology; D011090:Polyenes / Q000494:pharmacology*; D020123:Sirolimus; D012964:Sodium / Q000378:metabolism*; D016559:Tacrolimus / Q000494:pharmacology*; D013997:Time Factors
D007166:Immunosuppressive Agents; D000451:Mineralocorticoid Receptor Antagonists; D011090:Polyenes; D009761:Nystatin; D000450:Aldosterone; D016572:Cyclosporine; D012964:Sodium; D020123:Sirolimus; D016559:Tacrolimus