Cyclosporine A suppresses cyclooxygenase-2 expression in the rat kidney.
On the basis of recent evidence that the cyclooxygenase-2 (COX-2) gene promoter contains functional binding sites for the nuclear factor of activated T cells (NFAT) and that COX-2 is expressed in a regulated fashion in the kidney, this study aimed to assess the effect of immunosuppressants on COX-2 expression in the kidney. Therefore, Wistar-Kyoto rats were treated with cyclosporine A (CsA; 15 mg/kg per day) or tacrolimus (5 mg/kg per day) for 7 d each. Both drugs markedly lowered COX-2 expression while COX-1 expression remained unaltered. Furthermore, CsA blunted the increase of renocortical COX-2 expression in response to low salt intake or a combination of low-salt diet with the ACE inhibitor ramipril (10 mg/kg per day), which strongly stimulates renocortical COX-2 expression. At the same time, calcineurin inhibitors moderately enhanced basal as well as stimulated renin secretion and renin gene expression. These findings suggest that inhibition of calcineurin could be a crucial determinant for the regulated expression of COX-2 in the kidney. Inhibition of COX-2 expression may therefore at least in part account for the well-known adverse effects of immunosuppressants in the kidney. Moreover, our data suggest that the stimulation of the renin system by low salt and by ACE inhibitors is not essentially mediated by COX-2 activity.
Höcherl
Klaus
K
Institut für Pharmakologie, University of Regensburg, Regensburg, Germany. klaus.hoecherl@chemie.uni-regensburg.de
Dreher
Franziska
F
Vitzthum
Helga
H
Köhler
Jens
J
Kurtz
Armin
A
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D051546:Cyclooxygenase 2; D016572:Cyclosporine / Q000494:pharmacology*; D004039:Diet, Sodium-Restricted; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000235:genetics; D007668:Kidney / Q000201:enzymology* / Q000378:metabolism; D007672:Kidney Cortex / Q000201:enzymology; D008297:Male; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D017257:Ramipril / Q000494:pharmacology; D051381:Rats; D011921:Rats, Inbred WKY; D012083:Renin / Q000235:genetics / Q000378:metabolism; D016559:Tacrolimus / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000235:genetics; D053773:Transforming Growth Factor beta1
D000806:Angiotensin-Converting Enzyme Inhibitors; D007166:Immunosuppressive Agents; D007527:Isoenzymes; D012333:RNA, Messenger; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D016572:Cyclosporine; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D012083:Renin; D017257:Ramipril; D016559:Tacrolimus