Fuller, T. F., Kusch, A., Chaykovska, L., Catar, R., Pützer, J., Haller, M., Troppmair, J., Hoff, U. and Dragun, D. (2012) Protein kinase C inhibition ameliorates posttransplantation preservation injury in rat renal transplants. Transplantation, 94(7), pp. 679-686. (doi: 10.1097/TP.0b013e318265c4d8)
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Publisher's URL: http://dx.doi.org/10.1097/TP.0b013e318265c4d8
Abstract
BACKGROUND: Prolonged cold preservation frequently causes delayed renal graft function resulting from tubular epithelial injury. Inhibition of signal transduction downstream from protein kinase C (PKC) may reduce renal ischemia-reperfusion injury and confer renal graft protection. We therefore evaluated the effect of sotrastaurin, a small-molecule inhibitor of Ca<sup>²⁺</sup>-dependent and Ca<sup>²⁺</sup>-independent PKC isoforms, in comparison with mycophenolic acid (MPA) on rat renal transplants with prolonged cold preservation.<p></p> METHODS: Donor kidneys from male Lewis rats were cold stored in University of Wisconsin solution for 24 hr before syngeneic grafting. Recipients received sotrastaurin (30 mg/kg twice daily), MPA (20 mg/kg/day), or vehicle through gavage starting 1 hr after surgery. Renal function was evaluated by serum creatinine and histology on day 2 (acute injury) and day 7 (repair phase) after transplantation. Postreperfusion inflammation was determined by real-time polymerase chain reaction of proinflammatory genes and histology. Signaling mechanisms were studied by Western blotting and immunohistochemistry.<p></p> RESULTS: Sotrastaurin enhanced immediate transplant function, attenuated epithelial injury, and accelerated renal function recovery compared with MPA. Despite the stronger anti-inflammatory capacity of MPA, only sotrastaurin treatment achieved significant cellular protection with persisting reduced apoptosis of tubular epithelial cells. Decreased phosphorylation of extracellular signal-regulated protein kinase and p66Shc adaptor protein, both involved in cellular stress and apoptosis, were likely the responsible mechanism of action.<p></p> CONCLUSIONS: The PKC inhibitor sotrastaurin effectively ameliorated ischemia-reperfusion organ damage and promoted cytoprotection in a clinically relevant model of extended renal cold preservation followed by transplantation. Pharmacologic targeting of PKC may be beneficial for recipients receiving renal transplants at risk for delayed graft function.<p></p>
Item Type: | Articles |
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Status: | Published |
Refereed: | Yes |
Glasgow Author(s) Enlighten ID: | Haller, Ms Martina |
Authors: | Fuller, T. F., Kusch, A., Chaykovska, L., Catar, R., Pützer, J., Haller, M., Troppmair, J., Hoff, U., and Dragun, D. |
College/School: | College of Medical Veterinary and Life Sciences > School of Cancer Sciences |
Journal Name: | Transplantation |
ISSN: | 0041-1337 |
ISSN (Online): | 1534-6080 |
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