Heme oxygenase-1 attenuates ischemia/reperfusion-induced apoptosis and improves survival in rat renal allografts.
BACKGROUND
Kidneys can be preserved only for a limited time without jeopardizing graft function and survival. Induction of heat shock proteins (HSPs) can protect against ischemia/reperfusion (I/R) injury. Therefore, we investigated whether the induction of the HSP, heme oxygenase-1 (HO-1), improves outcome following isotransplantation after an extended period of cold storage.


METHODS
Rats were subjected to heat preconditioning (HP; 42 degrees C for 20 minutes). Kidneys harvested after 24 hours, were preserved in cold University of Wisconsin (UW) solution at 4 degrees C for 45 hours and transplanted into bilateral nephrectomized rats. Cobalt protoporphyrin (CoPP) was administered in another group of animals in order to induce HO-1 pharmacologically, while other groups of animals received the HO-1 inhibitor, tin protophorphyrine (SnPP), following HP or CoPP.


RESULTS
Cold ischemia caused a complete attenuation of graft function within 3 days following transplantation and subsequent death of all animals, whereas HP protected graft function and five of nine rats survived for 3 weeks. HP inhibited the induction of osteopontin and induced the expression of HO-1, HSP 70 and 90, and the antiapoptotic factor Bcl-XL. Grafts exposed to HP were protected against structural I/R injuries as revealed by histologic assessment using a semiquantitative score. Furthermore, induction of apoptosis was attenuated and activation of caspase-3 was inhibited. Comparable results were observed after administration of CoPP, whereas SnPP inhibited the effects of HP and CoPP.


CONCLUSIONS
HP or administration of CoPP induced both HO-1, preserved kidney graft function, and prevented postreperfusion apoptosis after cold preservation.
Wagner
Markus
M
Department of Visceral and Transplantation Surgery, University of Bern, Bern, Switzerland.
Cadetg
Petra
P
Ruf
Rainer
R
Mazzucchelli
Luca
L
Ferrari
Paolo
P
Redaelli
Claudio A
CA
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D003080:Cold Temperature; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006085:Graft Survival; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051547:Heme Oxygenase-1; D006358:Hot Temperature; D015151:Immunoblotting; D020287:In Situ Nick-End Labeling; D019194:Ischemic Preconditioning; D007668:Kidney / Q000502:physiology; D007676:Kidney Failure, Chronic / Q000401:mortality / Q000601:surgery; D016030:Kidney Transplantation; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology; D053495:Osteopontin; D011524:Protoporphyrins / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D015427:Reperfusion Injury / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D012795:Sialoglycoproteins / Q000378:metabolism; D014184:Transplantation, Homologous
D004791:Enzyme Inhibitors; D008665:Metalloporphyrins; D011524:Protoporphyrins; D012795:Sialoglycoproteins; C506897:Spp1 protein, rat; D053495:Osteopontin; C007095:cobaltiprotoporphyrin; C032628:tin protoporphyrin IX; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases