title: 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.affiliation: Department of Urology, Charité-Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany.
authors.forename: Tom Florian
authors.initials: TF
authors.lastname: Fuller
authors.forename: Angelika
authors.initials: A
authors.lastname: Kusch
authors.forename: Lyubov
authors.initials: L
authors.lastname: Chaykovska
authors.forename: Rusan
authors.initials: R
authors.lastname: Catar
authors.forename: Jennifer
authors.initials: J
authors.lastname: Pützer
authors.forename: Martina
authors.initials: M
authors.lastname: Haller
authors.forename: Jakob
authors.initials: J
authors.lastname: Troppmair
authors.forename: Uwe
authors.initials: U
authors.lastname: Hoff
authors.forename: Duska
authors.initials: D
authors.lastname: Dragun
mesh_terms: D000241:Adenosine / Q000633:toxicity; D000493:Allopurinol / Q000633:toxicity; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000097:blood; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D003080:Cold Temperature / Q000009:adverse effects; D003404:Creatinine / Q000097:blood; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D019610:Cytoprotection; D051799:Delayed Graft Function / Q000097:blood / Q000201:enzymology / Q000209:etiology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D005978:Glutathione / Q000633:toxicity; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000378:metabolism; D007328:Insulin / Q000633:toxicity; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D016030:Kidney Transplantation / Q000009:adverse effects*; D008297:Male; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D009926:Organ Preservation / Q000009:adverse effects*; D019188:Organ Preservation Solutions / Q000633:toxicity; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D011887:Raffinose / Q000633:toxicity; D051381:Rats; D011917:Rats, Inbred Lew; D060888:Real-Time Polymerase Chain Reaction; D015427:Reperfusion Injury / Q000097:blood / Q000201:enzymology / Q000209:etiology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: D015415:Biomarkers; D016207:Cytokines; D018836:Inflammation Mediators; D007328:Insulin; D019188:Organ Preservation Solutions; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D011799:Quinazolines; C055206:University of Wisconsin-lactobionate solution; D000493:Allopurinol; C543528:sotrastaurin; D003404:Creatinine; D011493:Protein Kinase C; D005978:Glutathione; D009173:Mycophenolic Acid; D000241:Adenosine; D011887:Raffinose