| Renal tubular Fas ligand mediates fratricide in cisplatin-induced acute kidney failure. | |
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MedLine Citation:
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PMID: 20811331 Owner: NLM Status: In-Data-Review |
Abstract/OtherAbstract:
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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. |
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Authors:
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Andreas Linkermann; Nina Himmerkus; Lars Rölver; Kirsten A Keyser; Philip Steen; Jan-Hinrich Bräsen; Markus Bleich; Ulrich Kunzendorf; Stefan Krautwald |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-09-01 |
Journal Detail:
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Title: Kidney international Volume: 79 ISSN: 1523-1755 ISO Abbreviation: Kidney Int. Publication Date: 2011 Jan |
Date Detail:
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Created Date: 2010-12-30 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0323470 Medline TA: Kidney Int Country: United States |
Other Details:
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Languages: eng Pagination: 169-78 Citation Subset: IM |
Affiliation:
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Division of Nephrology and Hypertension, Christian-Albrechts University, Kiel, Germany. |
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Descriptor/Qualifier:
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| Comments/Corrections | |
Comment In:
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Kidney Int. 2011 Jan;79(2):149-50
[PMID:
21191389
]
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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