Nephrotoxicity of cyclosporin A and FK506: inhibition of calcineurin phosphatase.
Cyclosporin A (CsA; 50 mg/kg) and Fujimycine (FK506; 5 mg/kg), but not the related macrolide immunosuppressant rapamycin (5 mg/kg), caused a reduction of glomerular filtration rate, degenerative changes of proximal tubular epithelium, and hypertrophy of the juxtaglomerular apparatus in male Wistar rats when given for 10 days. The molecular mechanisms of CsA and FK506 toxicity were investigated. Cyclophilin A and FK506-binding protein, the main intracytoplasmic receptors for CsA and FK506, respectively, were each detected in renal tissue extract. In the kidney, high levels of immunoreactive and enzymatically active calcineurin were found which were inhibited by the immunosuppressants CsA and FK506, but not by rapamycin. Finally, specific immunophilin-drug-calcineurin complexes formed only in the presence of CsA and FK506, but not rapamycin. These results suggest that the nephrotoxic effects of CsA and FK506 is likely mediated through binding to renal immunophilin and inhibiting calcineurin phosphatase.
Su
Q
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Institute of Toxicology, University of Zürich, Schwerzenbach.
Weber
L
L
Le Hir
M
M
Zenke
G
G
Ryffel
B
B
D000818:Animals; D000935:Antifungal Agents / Q000378:metabolism / Q000633:toxicity; D015153:Blotting, Western; D019703:Calcineurin; D002148:Calmodulin-Binding Proteins / Q000037:antagonists & inhibitors*; D002352:Carrier Proteins / Q000378:metabolism; D003432:Cross-Linking Reagents; D016572:Cyclosporine / Q000378:metabolism / Q000633:toxicity*; D004268:DNA-Binding Proteins / Q000378:metabolism; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007668:Kidney / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology; D008297:Male; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors*; D011090:Polyenes / Q000378:metabolism / Q000633:toxicity; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D020123:Sirolimus; D016559:Tacrolimus / Q000378:metabolism / Q000633:toxicity*; D022021:Tacrolimus Binding Proteins
D000935:Antifungal Agents; D002148:Calmodulin-Binding Proteins; D002352:Carrier Proteins; D003432:Cross-Linking Reagents; D004268:DNA-Binding Proteins; D006360:Heat-Shock Proteins; D011090:Polyenes; D016572:Cyclosporine; D019703:Calcineurin; D010749:Phosphoprotein Phosphatases; D022021:Tacrolimus Binding Proteins; D020123:Sirolimus; D016559:Tacrolimus