|Protein kinase C inhibition ameliorates posttransplantation preservation injury in rat renal transplants.|
|PMID: 22932117 Owner: NLM Status: MEDLINE|
|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 Ca²⁺-dependent and Ca²⁺-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.
|Tom Florian Fuller; Angelika Kusch; Lyubov Chaykovska; Rusan Catar; Jennifer Pützer; Martina Haller; Jakob Troppmair; Uwe Hoff; Duska Dragun|
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|Type: Comparative Study; Journal Article; Research Support, Non-U.S. Gov't|
|Title: Transplantation Volume: 94 ISSN: 1534-6080 ISO Abbreviation: Transplantation Publication Date: 2012 Oct|
|Created Date: 2012-10-05 Completed Date: 2012-12-21 Revised Date: 2013-05-29|
Medline Journal Info:
|Nlm Unique ID: 0132144 Medline TA: Transplantation Country: United States|
|Languages: eng Pagination: 679-86 Citation Subset: IM|
|Department of Urology, Charité-Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany.|
|APA/MLA Format Download EndNote Download BibTex|
Allopurinol / toxicity
Apoptosis / drug effects
Biological Markers / blood
Cell Proliferation / drug effects
Cold Temperature / adverse effects
Creatinine / blood
Cytokines / genetics, metabolism
Delayed Graft Function / blood, enzymology, etiology, genetics, pathology, prevention & control*
Glutathione / toxicity
Inflammation Mediators / metabolism
Insulin / toxicity
Kidney / drug effects*, enzymology, pathology
Kidney Transplantation / adverse effects*
Mycophenolic Acid / analogs & derivatives, pharmacology
Organ Preservation / adverse effects*
Organ Preservation Solutions / toxicity
Protein Kinase C / antagonists & inhibitors*, metabolism
Protein Kinase Inhibitors / pharmacology*
Pyrroles / pharmacology*
Quinazolines / pharmacology*
Raffinose / toxicity
Rats, Inbred Lew
Real-Time Polymerase Chain Reaction
Reperfusion Injury / blood, enzymology, etiology, genetics, pathology, prevention & control*
Signal Transduction / drug effects
|0/Biological Markers; 0/Cytokines; 0/Inflammation Mediators; 0/Insulin; 0/Organ Preservation Solutions; 0/Protein Kinase Inhibitors; 0/Pyrroles; 0/Quinazolines; 0/University of Wisconsin-lactobionate solution; 24280-93-1/Mycophenolic Acid; 315-30-0/Allopurinol; 512-69-6/Raffinose; 58-61-7/Adenosine; 60-27-5/Creatinine; 70-18-8/Glutathione; 7I279E1NZ8/sotrastaurin; 9242ECW6R0/mycophenolate mofetil; EC 184.108.40.206/Protein Kinase C|
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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