Epithelial-to-mesenchymal transition of human proximal tubular epithelial cells: effects of rapamycin, mycophenolate, cyclosporin, azathioprine, and methylprednisolone.
Epithelial-to-mesenchymal transition (EMT) of renal proximal tubular epithelial cells (PTEC) into myofibroblasts is an important step in the pathogenesis of chronic allograft nephropathy. The effects of commonly used immunosuppressives in renal transplantation on EMT are not known. PTEC were cultured in transforming growth factor-beta to induce EMT. The effects of the immunosuppressives on cell morphology and alpha-smooth muscle actin were studied by phase contrast microscopy, immunocytochemistry, and western blotting. The effects on versican were studied by [S] labeling and polyacrylamide gel electrophoresis. Rapamycin and mycophenolate mofetil (MMF) prevented EMT and moreover returned myofibroblasts to PTEC morphology. These immunosuppressives also reduced versican production by both PTEC and myofibroblasts. Cyclosporine A, azathioprine, and methylprednisolone were less effective than rapamycin and MMF. Moreover, these immunosuppressives did not decrease versican. Rapamycin and MMF have a greater inhibitory effect on EMT in vitro than older immunosuppressives and may result in less fibrosis and a better long-term allograft survival.
Copeland
Justin W G V
JW
Department of Renal Medicine, Auckland City Hospital, Auckland, New Zealand.
Beaumont
Brent W
BW
Merrilees
Mervyn J
MJ
Pilmore
Helen L
HL
D000199:Actins / Q000378:metabolism; D001379:Azathioprine / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D016030:Kidney Transplantation / Q000379:methods; D007687:Kidney Tubules, Proximal / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D008775:Methylprednisolone / Q000494:pharmacology; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D020123:Sirolimus / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D053675:Versicans / Q000378:metabolism
D000199:Actins; D007166:Immunosuppressive Agents; D016212:Transforming Growth Factor beta; D053675:Versicans; D016572:Cyclosporine; D009173:Mycophenolic Acid; D001379:Azathioprine; D020123:Sirolimus; D008775:Methylprednisolone