Mitochondrial tyrosine nitration precedes chronic allograft nephropathy.
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.
MacMillan-Crow
L A
LA
Department of Surgery, UAB School of Medicine, Birmingham, AL 35294, USA. lmcrow@ccc.uab.edu
Cruthirds
D L
DL
Ahki
K M
KM
Sanders
P W
PW
Thompson
J A
JA
D000818:Animals; D002908:Chronic Disease; D003574:Cytochrome c Group / Q000378:metabolism; D006084:Graft Rejection / Q000473:pathology; D016030:Kidney Transplantation / Q000473:pathology; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism*; D023421:Models, Animal; D030421:Peroxynitrous Acid / Q000096:biosynthesis*; D051381:Rats; D026361:Reactive Nitrogen Species / Q000096:biosynthesis; D051437:Renal Insufficiency / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D013482:Superoxide Dismutase / Q000378:metabolism; D014184:Transplantation, Homologous / Q000009:adverse effects*; D014443:Tyrosine / Q000378:metabolism*
D003574:Cytochrome c Group; D026361:Reactive Nitrogen Species; D030421:Peroxynitrous Acid; D014443:Tyrosine; D013482:Superoxide Dismutase