Protein kinase C inhibition ameliorates posttransplantation preservation injury in rat renal transplants.

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 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
• Journal: Transplantation (Transplantation) Vol. 94 Issue 7 Pg. 679-86 (Oct 15 2012) ISSN: 1534-6080 [Electronic] United States
• PMID: 22932117 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers
• Cytokines
• Inflammation Mediators
• Insulin
• Organ Preservation Solutions
• Protein Kinase Inhibitors
• Pyrroles
• Quinazolines
• University of Wisconsin-lactobionate solution
• Allopurinol
• sotrastaurin
• Creatinine
• Protein Kinase C
• Glutathione
• Mycophenolic Acid
• Adenosine
• Raffinose

Topics

• Adenosine (toxicity)
• Allopurinol (toxicity)
• Animals
• Apoptosis (drug effects)
• Biomarkers (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