Document Detail


Protein kinase C inhibition ameliorates posttransplantation preservation injury in rat renal transplants.
MedLine Citation:
PMID:  22932117     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Tom Florian Fuller; Angelika Kusch; Lyubov Chaykovska; Rusan Catar; Jennifer Pützer; Martina Haller; Jakob Troppmair; Uwe Hoff; Duska Dragun
Related Documents :
24629357 - Epr spectroscopy as a predictive tool for the assessment of marginal donor livers perfu...
24157027 - Characteristics of recipients who achieved spontaneous operational tolerance in adult l...
24382837 - Antibody-mediated rejection as a contributor to previously unexplained early liver allo...
23186707 - Transplantation in the future.
22564577 - Endomyocardial biopsy in heart transplantation: schedule or event?
3398137 - Adult segmental cystic disease of the kidney: a renal-sparing management approach.
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    
Affiliation:
Department of Urology, Charité-Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Adenosine / toxicity
Allopurinol / toxicity
Animals
Apoptosis / drug effects
Biological Markers / blood
Blotting, Western
Cell Proliferation / drug effects
Cold Temperature / adverse effects
Creatinine / blood
Cytokines / genetics,  metabolism
Cytoprotection
Delayed Graft Function / blood,  enzymology,  etiology,  genetics,  pathology,  prevention & control*
Glutathione / toxicity
Immunohistochemistry
Inflammation Mediators / metabolism
Insulin / toxicity
Kidney / drug effects*,  enzymology,  pathology
Kidney Transplantation / adverse effects*
Male
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
Rats, Inbred Lew
Real-Time Polymerase Chain Reaction
Reperfusion Injury / blood,  enzymology,  etiology,  genetics,  pathology,  prevention & control*
Signal Transduction / drug effects
Time Factors
Chemical
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 2.7.11.13/Protein Kinase C

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


Previous Document:  Recipient age and time spent hospitalized in the year before and after kidney transplantation.
Next Document:  Vitamin D receptor agonists increase klotho and osteopontin while decreasing aortic calcification in...