Nephrotoxicity of immunosuppressants in rats: comparison of macrolides with cyclosporin.
The nephrotoxic potential of the macrolide immunosuppressants, FK506 and rapamycin, was compared with that of cyclosporin (CsA) in male Wistar rats. FK506 induced a reduction of creatinine clearance, hypomagnesemia and hyperuricemia as previously described for CsA. In contrast, equidosed rapamycin did not alter the glomerular filtration rate. FK506 caused proximal tubular epithelial changes consisting of atrophy, vacuolization, inclusion bodies, microcalcification and focal mononuclear interstitial infiltrate as described for CsA. The most striking alteration was hypertrophy of the juxtaglomerular apparatus (JGA). The percentage of renin-containing JGA and the extent of renin immunoreactivity along afferent vessels were significantly increased in FK506- and CsA-treated rats. By contrast, no renal morphologic lesions were found in rapamycin-treated animals. Renal cortical extracts contained abundant cyclophilin and FK506-binding protein (FKBP), the main intracytoplasmic receptors for CsA and FK506, respectively. Furthermore, we demonstrated that receptor bound CsA and FK506, but not rapamycin, formed complexes with the phosphatase calcineurin, as shown previously for lymphocytes. Thus, it is hypothesized that both the immunosuppressive and toxic effects of FK506 and CsA, but not of rapamycin, are mediated through an immunophilin-drug-calcineurin complex. The renal substrate of calcineurin, which mediates renal vasoconstriction is yet to be identified.
Ryffel
B
B
Institute of Toxicology, University of Zürich, Schwerzenbach.
Weber
E
E
Mihatsch
M J
MJ
D000591:Amino Acid Isomerases / Q000378:metabolism; D000818:Animals; D019703:Calcineurin; D002148:Calmodulin-Binding Proteins / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D016572:Cyclosporine / Q000633:toxicity*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004573:Electrolytes / Q000097:blood / Q000652:urine; D016232:Endothelins / Q000096:biosynthesis / Q000187:drug effects; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects* / Q000502:physiology / Q000648:ultrastructure; D007684:Kidney Tubules / Q000187:drug effects / Q000648:ultrastructure; D008297:Male; D008854:Microscopy, Electron; D019696:Peptidylprolyl Isomerase; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D011090:Polyenes / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D012083:Renin / Q000096:biosynthesis / Q000187:drug effects; D020123:Sirolimus; D016559:Tacrolimus / Q000633:toxicity*; D022021:Tacrolimus Binding Proteins
D002148:Calmodulin-Binding Proteins; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D004573:Electrolytes; D016232:Endothelins; D006360:Heat-Shock Proteins; D007166:Immunosuppressive Agents; D011090:Polyenes; D016572:Cyclosporine; D019703:Calcineurin; D010749:Phosphoprotein Phosphatases; D012083:Renin; D000591:Amino Acid Isomerases; D022021:Tacrolimus Binding Proteins; D019696:Peptidylprolyl Isomerase; D020123:Sirolimus; D016559:Tacrolimus