Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 31, Issue 12, Pages 1603-1608Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/S0891-5849(01)00750-X
Keywords
tyrosine nitration; MnSOD; cytochrome c; peroxynitrite; chronic allograft nephropathy (CAN); transplantation; kidney; rat; mitochondria; free radicals
Funding
- NHLBI NIH HHS [HL45990] Funding Source: Medline
- NIDDK NIH HHS [DK46199, DK51629] Funding Source: Medline
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Endogenous tyrosine nitration and inactivation of manganese superoxide dismutase (MnSOD) has previously been reported to occur during end-stage human renal allograft rejection. In order to determine whether nitration and inactivation of this critical mitochondrial protein might play a contributory role in the onset of transplant rejection, we employed a rodent model of Chronic Allograft Nephropathy (or CAN). Using this model we followed kidney function from 2-52 weeks post-transplant and correlated graft function with levels of nitration in the renal allograft. Tyrosine nitration of both glomerular and tubular structures occurred at 2 weeks post-transplant. At later times (16 weeks) post-transplant, tyrosine nitration appeared to be confined to tubular structures; however glomerular nitration returned at 52 weeks post-transplant. Interestingly, nitration and inactivation of MnSOD occurs prior to the onset of renal dysfunction in this rat model of chronic allograft nephropathy (2 weeks versus 16 weeks post-transplant). Furthermore, we have identified an additional mitochondrial protein, cytochrome c, as being endogenously nitrated during chronic rejection. The kinetics of cytochrome c nitration lagged behind MnSOD nitration and inactivation (4 weeks compared to 2 weeks); suggesting that loss of MnSOD activity likely contributes to elevation of the nitrating species and further nitration of other targets. (C) 2001 Elsevier Science Inc.
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