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

Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association
María PérezAlberto Tejedor

Abstract

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. 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. 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...Continue Reading

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Citations

Oct 31, 2007·Apoptosis : an International Journal on Programmed Cell Death·H ServaisM-P Mingeot-Leclercq
Sep 28, 2006·Clinical and Experimental Pharmacology & Physiology·Sam HarirforooshFakhreddin Jamali
Dec 9, 2010·Basic & Clinical Pharmacology & Toxicology·Mahmoud M Mohy El-DinHeba A Abd El Razik
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Jul 28, 2018·Journal of Lipid Research·Estefanía Moreno-GordalizaM Milagros Gómez-Gómez
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Jul 16, 2020·Expert Opinion on Drug Safety·Mersedeh Shayan, Sepideh Elyasi
May 23, 2020·International Journal of Molecular Sciences·Yu Ah HongHyeon Seok Hwang
Oct 31, 2020·Clinical Kidney Journal·Alberto Ortiz
Jan 31, 2021·International Journal of Molecular Sciences·Matilde ZaballosLuis González-Bayón

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Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis