| Protein Kinase C Inhibition Ameliorates Posttransplantation Preservation Injury in Rat Renal Transplants. | |
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MedLine Citation:
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PMID: 22932117 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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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-dependent and Ca-independent PKC isoforms, in comparison with mycophenolic acid (MPA) on rat renal transplants with prolonged cold preservation. 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. 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. 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. |
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Authors:
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Tom Florian Fuller; Angelika Kusch; Lyubov Chaykovska; Rusan Catar; Jennifer Pützer; Martina Haller; Jakob Troppmair; Uwe Hoff; Duska Dragun |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-8-28 |
Journal Detail:
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Title: Transplantation Volume: - ISSN: 1534-6080 ISO Abbreviation: Transplantation Publication Date: 2012 Aug |
Date Detail:
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Created Date: 2012-8-30 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0132144 Medline TA: Transplantation Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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1 Department of Urology, Charité - Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany. 2 Department of Nephrology and Intensive Care Medicine, Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany. 3 Center for Cardiovascular Research, Charité - Universitätsmedizin Berlin, Berlin, Germany. 4 Clinic for Cardiovascular Surgery, University Hospital Zurich, Zurich, Switzerland. 5 Daniel-Swarovski-Research Laboratory, Department of Visceral, Transplant and Thoracic Surgery, Innsbruck Medical University, Innsbruck, Austria. 6 Address correspondence to: Dr. Duska Dragun, Department of Nephrology and Intensive Care Medicine, Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum, Augustenburger Platz 1, D-13353 Berlin, Germany. |
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