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NDT Advance Access originally published online on July 13, 2004
Nephrology Dialysis Transplantation 2004 19(10):2445-2455; doi:10.1093/ndt/gfh397
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Nephrol Dial Transplant Vol. 19 No. 10 © ERA-EDTA 2004; all rights reserved

Original Article

Inhibition of brush border dipeptidase with cilastatin reduces toxic accumulation of cyclosporin A in kidney proximal tubule epithelial cells

María Pérez1, Manuela Castilla1, Ana María Torres1, Jose Antonio Lázaro1, Elisabeth Sarmiento2 and Alberto Tejedor1

1 Department of Nephrology and 2 Department of Immunology Laboratory of Renal Physiopathology, Hospital General Universitario Gregorio Marañón, Madrid, Spain

Correspondence and offprint requests to: Dr Alberto Tejedor, Department of Nephrology, Laboratory of Renal Physiopathology, Hospital General Universitario Gregorio Marañón, Doctor Esquerdo 46, 28007 Madrid, Spain. Email: atejedor{at}nefro.hggm.es

Background. Cilastatin reduces nephrotoxicity associated with cyclosporin A (CyA) in solid organ and bone marrow transplantation. This appears to be unrelated to changes in renal haemodynamics or CyA metabolism. How cilastatin induces this protection is unclear, but it could result from changes on accumulation of CyA proximal cells.

Methods. We investigated the effects of cilastatin on primary cultures of pig kidney proximal tubule epithelial cells (PTECs) treated with CyA and FK506. Cell membrane fluidity and membrane-bound cholesterol-rich raft (MBCR) distribution were evaluated by fluorescence microscopy, and CyA transport by radioimmunoassay. Changes in CyA- and FK506-induced apoptosis were also evaluated by electron and light microscopy, flow cytometry, and detection of cytoplasmic nucleosones by enzyme-linked immuosorbent assay.

Results. CyA caused a dose-dependent reduction of cell membrane fluidity, which was prevented by pre-treating PTECs with cilastatin. Cilastatin also inhibited CyA transport across membranes and reduced recovery of CyA in mitochondria and membrane-bound fractions from cilastatin-treated PTECs. This effect was not related to an altered distribution of MBCRs, which are essential for CyA transport. Cilastatin protected against CyA- and FK506-induced apoptosis.

Conclusions. Prevention of CyA-induced reduction of cell membrane fluidity and inhibition of CyA transport are features of cilastatin's direct effects on PTECs. Unaltered distribution of MBCRs in the presence of cilastatin suggests that cilastatin binding to raft-bound dipeptidases, rather than MBCR modifications, causes interference with CyA transport. These results provide additional insight into the mechanisms and scope of cilastatin nephroprotection.

Keywords: cilastatin; cyclosporin A; dipeptidase; FK506; proximal tubule cells; raft


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