Both Darbepoetin Alfa and carbamylated erythropoietin prevent kidney graft dysfunction due to ischemia/reperfusion in rats

Paola Cassis, Nadia Azzollini, Samantha Solini, Marilena Mister, Sistiana Aiello, Daniela Cugini, Pierangela Scudeletti, Elena Gagliardini, Mauro Abbate, Lorenzo Gallon, Giuseppe Remuzzi*, Marina Noris

*Corresponding author for this work

Research output: Contribution to journalArticle

21 Scopus citations

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. Conclusion: 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.

Original languageEnglish (US)
Pages (from-to)271-279
Number of pages9
JournalTransplantation
Volume92
Issue number3
DOIs
StatePublished - Aug 15 2011

Keywords

  • Erythropoietin
  • Ischemia/reperfusion
  • Kidney transplant
  • Oxidative stress
  • Peritubular capillaries

ASJC Scopus subject areas

  • Transplantation

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