title: Both darbepoetin alfa and carbamylated erythropoietin prevent kidney graft dysfunction due to ischemia/reperfusion in rats.
abstract: BACKGROUND
  Ischemia/reperfusion (I/R) injury is an important cause of renal graft dysfunction. Increases in cold and warm ischemia times lead to a higher risk of early posttransplant complications including delayed graft function and acute rejection. Moreover, prolonged cold ischemia is a predictor of long-term graft loss in kidney transplant patients.
  
  
  METHODS
  Darbepoetin alfa (DA) and carbamylated nonerythropoietic derivative of erythropoietin (CEPO) protective effects were evaluated in a model of I/R injury after kidney transplantation in both syngeneic and allogeneic combinations. The effects of wortmannin (phosphorylated Akt [p-Akt] inhibitor) administration were also investigated. Serum creatinine was evaluated at 16, 24, 48 hr and at 4 and 7 days posttransplant. Animals were killed 24 hr or 7 days after transplant and kidneys were processed for histological analysis, immunohistochemistry assessment of erythropoietin receptor (EPOR) and β-common chain receptor expression, granulocyte infiltration, nitrotyrosine staining, p-Akt expression, peritubular capillary (PTC) density, apoptosis, antioxidant, and antiapoptotic gene expression.
  
  
  RESULTS
  DA and CEPO significantly reduced serum creatinine, tubular injury, tubular nitrotyrosine staining, and prevented I/R-induced tubular apoptosis, but only when given both to the donor and to the recipient. DA and CEPO cytoprotection was associated with prevention of I/R-induced drop of p-Akt expression in tubuli, and almost complete preservation of capillary density in the tubulointerstitium of the graft. CEPO was more effective than DA in reducing tubular oxidative stress and preserving PTCs.
  
  
  CONCLUSIONS
  DA and CEPO when given both to the donor and to the recipient, prevented renal graft dysfunction, tubular oxidative stress, and apoptosis after I/R injury in kidney transplantation. Their cytoprotection was mediated by tubular p-Akt activation and PTC density preservation.
authors.affiliation: Transplant Research Center, Chiara Cucchi De Alessandri & Gilberto Crespi Mario Negri Institute for Pharmacological Research, Via Camozzi, Bergamo, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Cassis
authors.forename: Nadia
authors.initials: N
authors.lastname: Azzollini
authors.forename: Samantha
authors.initials: S
authors.lastname: Solini
authors.forename: Marilena
authors.initials: M
authors.lastname: Mister
authors.forename: Sistiana
authors.initials: S
authors.lastname: Aiello
authors.forename: Daniela
authors.initials: D
authors.lastname: Cugini
authors.forename: Pierangela
authors.initials: P
authors.lastname: Scudeletti
authors.forename: Elena
authors.initials: E
authors.lastname: Gagliardini
authors.forename: Mauro
authors.initials: M
authors.lastname: Abbate
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Gallon
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Remuzzi
authors.forename: Marina
authors.initials: M
authors.lastname: Noris
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D003080:Cold Temperature; D000068256:Darbepoetin alfa; D004921:Erythropoietin / Q000031:analogs & derivatives* / Q000494:pharmacology; D006085:Graft Survival / Q000187:drug effects; D006397:Hematinics / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D016030:Kidney Transplantation; D007684:Kidney Tubules / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D055031:Primary Graft Dysfunction / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D015427:Reperfusion Injury / Q000188:drug therapy*; D014019:Tissue Donors; D014184:Transplantation, Homologous; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D000975:Antioxidants; D051017:Apoptosis Regulatory Proteins; D006397:Hematinics; D007166:Immunosuppressive Agents; C488171:carbamylated erythropoietin; D004921:Erythropoietin; D000068256:Darbepoetin alfa; C494920:Akt1 protein, rat; D051057:Proto-Oncogene Proteins c-akt; D000077191:Wortmannin