Role of xanthine oxidoreductase in experimental acute renal-allograft rejection.
BACKGROUND
Increased oxygen radical production may not only contribute to posttransplant ischemia-reperfusion injury but also to acute rejection of renal allografts. Xanthine oxidoreductase (XOR) may constitute a relevant reactive oxygen species (ROS) source. The study was conducted (1). to determine ROS production as well as oxidant and antioxidant enzyme activities in renal grafts and (2). to modulate acute rejection by tungsten administration, a specific inhibitor of XOR.


METHODS
Syngraft (Lewis to Lewis, Fisher344 to Fisher344) and allograft (Fisher344 to Lewis) kidney transplantations were performed with or without tungsten administration. Analysis was performed at day 1, 3, or 9 posttransplantation.


RESULTS
Generation of ROS was enhanced, being 10-fold higher in renal allografts versus control kidneys at day 9 (P <0.01); this was associated with histologic signs of acute rejection. Oxygen radicals were generated to a significant degree by enhanced XOR activity, which increased more than 10-fold in renal allografts at day 9 posttransplantation; XOR protein in glomeruli and tubulointerstitium was also elevated in allo-grafts. In addition, NADPH oxidase activity increased significantly in allografts. The activity of antioxidant enzymes tended to decrease. Tungsten treatment resulted in a pronounced reduction of XOR activity and ROS production, without any effect on NADPH-oxidase activity; mononuclear cell infiltration and rejection signs were significantly ameliorated at day 9 post-transplantation by selective inhibition of XOR.


CONCLUSIONS
A major part of ROS generation in acute rejection was contributed by XOR. ROS are not only associated with but also contribute to acute allograft rejection because inhibition of XOR alleviated rejection phenomena.
Sun
Kai
K
Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany.
Kiss
Eva
E
Bedke
Jens
J
Stojanovic
Tomislav
T
Li
Yanhua
Y
Gwinner
Wilfried
W
Gröne
Hermann-Josef
HJ
D000208:Acute Disease; D000818:Animals; D002374:Catalase / Q000378:metabolism; D006084:Graft Rejection / Q000503:physiopathology*; D007668:Kidney / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology; D016030:Kidney Transplantation; D007684:Kidney Tubules / Q000378:metabolism / Q000473:pathology; D009097:Multienzyme Complexes / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D009393:Nephritis / Q000473:pathology; D010088:Oxidoreductases / Q000378:metabolism; D011184:Postoperative Period; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D017382:Reactive Oxygen Species / Q000378:metabolism; D014184:Transplantation, Homologous; D014185:Transplantation, Isogeneic; D014414:Tungsten / Q000494:pharmacology; D014968:Xanthine Dehydrogenase / Q000378:metabolism*
D009097:Multienzyme Complexes; D017382:Reactive Oxygen Species; D010088:Oxidoreductases; D002374:Catalase; D014968:Xanthine Dehydrogenase; C023107:NADH oxidase; D009247:NADH, NADPH Oxidoreductases; D019255:NADPH Oxidases; D014414:Tungsten