Renal tubular epithelial cell apoptosis by Fas-FasL-dependent self-injury can augment renal allograft injury.
The role of Fas-FasL interactions in kidney allograft injury may be complex as renal tubular epithelial cells (TEC) express both Fas and FasL. The role and regulation of TEC self-injury has not been investigated. In co-cultures of TEC, FasL-bearing, Fas-null TEC was demonstrated to induce apoptosis of TEC-bearing Fas. Co-culturing effector lpr-TEC (M3.1-lpr) with target WT-TEC (CS3.7) at a ratio of 10:1 (E/T) induced 15.2 +/- 2.4% of target apoptosis as compared to its basal level of 2.6 +/- 0.3%. Similarly lpr-TEC induced apoptosis in gld-TEC (MRM-gld) from a basal level of 3.7 +/- 0.2% to 6.4 +/- 0.3%. Expression of kidney Fas-FasL on injury was tested in a renal transplant model. C57BL/6 (B6) mice were transplanted with Fas-deficient C3H-lpr/lpr or FasL mutation C3H-gld/gld kidneys as compared to normal (wild-type [WT]) C3H/Hej donors. Survival of both lpr and gld recipient was improved compared to WT donors (P <.05) as was function of lpr and gld kidneys indicated by a lower serum creatinine (LPR: 41 +/- 8 micromol/L; GLD: 52 +/- 7 micromol/L) as compared to the WT donors (84 +/- 8 micromol/L, P <.001). These results demonstrate that activated TEC may commit a novel and previously unreported form of self-injury (fractricide) through Fas-FasL. These results suggest that inhibition of renal Fas or FasL might be a useful strategy to prevent TEC loss during rejection.
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Lawson Health Research Institute, London Health Science Center, London, Ontario, Canada.
Guan
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Q
Yin
Z
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Masterson
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M
Zhong
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Jevnikar
A M
AM
D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D018920:Coculture Techniques; D053222:Fas Ligand Protein; D016030:Kidney Transplantation / Q000276:immunology; D007684:Kidney Tubules / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D008809:Mice, Inbred C3H; D019459:Urothelium / Q000276:immunology*; D019014:fas Receptor / Q000276:immunology*
D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D019014:fas Receptor