Renal tubular Fas ligand mediates fratricide in cisplatin-induced acute kidney failure

Linkermann, A., Himmerkus, N., Rolver, L., Keyser, K. A., Steen, P., Brasen, J. H., Bleich, M., Kunzendorf, U. and Krautwald, S. (2011) Renal tubular Fas ligand mediates fratricide in cisplatin-induced acute kidney failure Kidney International, 79 (2). pp. 169-178. DOI 10.1038/ki.2010.317.

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Cisplatin, a standard chemotherapeutic agent for many tumors, has an unfortunately common toxicity where almost a third of patients develop renal dysfunction after a single dose. Acute kidney injury caused by cisplatin depends on Fas-mediated apoptosis driven by Fas ligand (FasL) expressed on tubular epithelial and infiltrating immune cells. Since the role of FasL in T cells is known, we investigated whether its presence in primary kidney cells is needed for its toxic effect. We found that all cisplatin-treated wild-type (wt) mice died within 6 days; however, severe combined immunodeficiency (SCID)/beige mice (B-, T-, and natural killer-cell-deficient) displayed a significant survival benefit, with only 55 mortality while exhibiting significant renal failure. Treating SCID/beige mice with MFL3, a FasL-blocking monoclonal antibody, completely restored survival after an otherwise lethal cisplatin dose, suggesting another source of FasL besides immune cells. Freshly isolated primary tubule segments from wt mice were co-incubated with thick ascending limb (TAL) segments freshly isolated from mice expressing the green fluorescent protein (GFP) transgene (same genetic background) to determine whether FasL-mediated killing of tubular cells is an autocrine or paracrine mechanism. Cisplatin-stimulated primary segments induced apoptosis in the GFP-tagged TAL cells, an effect blocked by MFL3. Thus, our study shows that cisplatin-induced nephropathy is mediated through FasL, functionally expressed on tubular cells that are capable of inducing death of cells of adjacent tubules. Kidney International (2011) 79, 159-178; doi:10.1038/ki.2010.317; published online 1 September 2010

Document Type: Article
Keywords: acute kidney injury apoptosis cisplatin-induced nephropathy Fas ligand cell-death t-cells injury nephrotoxicity expression inhibition mechanisms apoptosis pathways therapy
Research affiliation: Kiel University
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Refereed: Yes
DOI etc.: 10.1038/ki.2010.317
ISSN: 0085-2538
Date Deposited: 01 Nov 2012 05:07
Last Modified: 15 Jan 2014 13:49

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