Document Detail

Protein kinase C inhibition ameliorates posttransplantation preservation injury in rat renal transplants.
MedLine Citation:
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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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Transplantation     Volume:  94     ISSN:  1534-6080     ISO Abbreviation:  Transplantation     Publication Date:  2012 Oct 
Date Detail:
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    
Other Details:
Languages:  eng     Pagination:  679-86     Citation Subset:  IM    
Department of Urology, Charité-Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany.
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MeSH Terms
Adenosine / toxicity
Allopurinol / toxicity
Apoptosis / drug effects
Biological Markers / blood
Blotting, Western
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
Time Factors
Reg. No./Substance:
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 Kinase C

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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