Renal tubular Fas ligand mediates fratricide in cisplatin-induced acute kidney failure.
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.
Linkermann
Andreas
A
Division of Nephrology and Hypertension, Christian-Albrechts University, Kiel, Germany.
Himmerkus
Nina
N
Rölver
Lars
L
Keyser
Kirsten A
KA
Steen
Philip
P
Bräsen
Jan-Hinrich
JH
Bleich
Markus
M
Kunzendorf
Ulrich
U
Krautwald
Stefan
S
D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000276:immunology* / Q000473:pathology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D017209:Apoptosis; D002945:Cisplatin / Q000633:toxicity*; D053222:Fas Ligand Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D007684:Kidney Tubules / Q000187:drug effects* / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D008822:Mice, Transgenic
D000911:Antibodies, Monoclonal; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D002945:Cisplatin