NOS2 (iNOS) deficiency in kidney donor accelerates allograft loss in a murine model.
Renal NOS2 is expressed and produces abundant nitric oxide (NO) in various renal cells in response to proinflammatory cytokines. However, the role of this enzyme in renal allograft survival remains unknown. Kidney allotransplantation was performed in the murine model of C57BL/6J (H-2(d)) to nephrectomized Balb/c (H-2(b)) mice. Here we show that deficiency in NOS2 expression in kidney donors significantly advanced allograft failure, indicated by decreasing mean survival of recipients receiving NOS2 null grafts (15.4 +/- 6.4 days) as compared to those with wild type grafts (65.4 +/- 28.1 days) (p = 0.0005). Consistent with survival results, NOS2 null grafts had more severe renal tubule injury and decreased renal function compared to wild type grafts. In vitro NOS2 expressing TEC had greater resistance to allogeneic lymphocyte-mediated apoptosis. The addition of exogenous NO inhibited Fas-mediated TEC apoptosis and reduced proliferation of allogeneic lymphocytes. These data suggest that endogenous production of NO through renal NOS2 activity can play a protective role in kidney grafts through attenuating Fas-mediated donor cell apoptosis as well as by inhibiting proliferation of inflammatory infiltrating lymphocytes. Enhanced donor NOS2 expression may be a useful strategy to improve kidney transplant survival.
Du
C
C
Department of Medicine, The University of Western Ontario, London, Ontario, Canada. dcaigan@uwo.ca
Jiang
J
J
Guan
Q
Q
Diao
H
H
Yin
Z
Z
Wang
S
S
Zhong
R
R
Jevnikar
A M
AM
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D006084:Graft Rejection / Q000201:enzymology / Q000209:etiology* / Q000276:immunology; D007668:Kidney / Q000201:enzymology; D016030:Kidney Transplantation / Q000276:immunology / Q000473:pathology*; D008214:Lymphocytes / Q000166:cytology / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000096:biosynthesis / Q000494:pharmacology; D052247:Nitric Oxide Synthase Type II / Q000172:deficiency / Q000502:physiology*; D015996:Survival Rate; D014019:Tissue Donors; D014184:Transplantation, Homologous; D019014:fas Receptor / Q000502:physiology
D019014:fas Receptor; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse