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This Article Full Text Full Text (PDF) All Versions of this Article: 286/5/F838    most recent 00230.2003v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Web of Science (7) Citing Articles via Google Scholar Google Scholar Articles by Mangino, M. J. Articles by Southard, J. H. Search for Related Content PubMed PubMed Citation Articles by Mangino, M. J. Articles by Southard, J. H.

Poly(ADP-ribose) polymerase and renal hypothermic preservation injury

¹Department of Surgery, University of Wisconsin, Madison, Wisconsin 53792; and ²Inotek Pharmaceuticals Corporation, Beverly, Massachusetts 01915

Submitted 24 June 2003 ; accepted in final form 18 December 2003

The nuclear enzyme poly(ADP-ribose) polymerase (PARP) has been implicated in ischemia-reperfusion injury in many tissues under normothermic conditions. The purpose of this study was to determine whether PARP contributes to mechanisms of the hypothermic ischemia-reperfusion injury that occurs when kidneys are cold stored for transplantation. Cortical tissue slice PARP enzyme activity rose significantly with prolonged cold storage and was dependent on both reperfusion and preservation quality. However, prior exposure to warm ischemia abrogated this increase. PARP protein increased with cold storage but was not dependent on reperfusion. PARP enzyme activity rose quickly after reperfusion in buffer and was not different when whole blood was used. Addition of exogenous hydrogen peroxide (3 mM) to normal renal slices significantly increased PARP activity over 4 h in the cortex but not in the medulla, but the medullary basal PARP synthesis rate was five times higher than that in the cortex. However, the reactive oxygen species (ROS) inhibitors catalase (2,000 U/ml), Trolox (200 µM), and DMSO (15 mM) did not reduce reperfusion-induced PARP activity in cold-stored cortical slices. Finally, PARP inhibitors potentiated preservation injury in isolated canine proximal renal tubules. In conclusion, canine renal PARP enzyme activity rises with prolonged cold storage after reperfusion and may play a protective rather than an injurious role in hypothermic preservation for transplantation. ROS are sufficient but not necessary to activate PARP under these conditions.

base excision system; NAD⁺; energy failure; adenosine 5'-triphosphate; reperfusion injury; pharmacological inhibition