NDT Advance Access originally published online on October 12, 2005
Nephrology Dialysis Transplantation 2006 21(2):330-336; doi:10.1093/ndt/gfi177
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© The Author [2005]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Original Articles: Experimental Nephrology
Erythropoietin attenuates renal injury in experimental acute renal failure ischaemic/reperfusion model
1 Department of Physiology, 3 Department of Pathology, Aristotle University of Thessaloniki and 2 Department of Nephrology, General Hospital of Veria, Greece
Correspondence and offprint requests to: D. Tsakiris, Department of Nephrology, General Hospital of Veria, Greece. Email: dimtsak{at}otenet.gr
Background. Erythropoietin (EPO), originally identified for its critical role in promoting erythrocyte survival and differentiation, has been shown to exert multiple paracrine/autocrine functions. Protective effects of EPO have been demonstrated in various tissues and experimental models of ischaemia-induced injury. In the present study, we investigated the effect of EPO on an in vivo rat model of renal ischaemia/reperfusion (I/R) injury and the possible mechanisms implicated in the EPO-mediated anti-apoptotic action.
Methods. Male Wistar rats, subjected to renal ischaemia for 45 min, were administered either saline or EPO (500 U/kg, i.p.) 20 min prior to I/R. A sham-operated group served as the control. At 48 h of reperfusion, the renal dysfunction and injury was assessed by measurement of serum biochemical markers (urea, creatinine) and histological grading. Apoptosis was assessed by the TUNEL method and morphological criteria. Expression of Bax and NF-
B (p65) was also evaluated.
Results. High levels of serum urea and creatinine were identified at 48 h after ischaemia. The EPO-treated group had significantly lower serum and creatinine levels. Semi-quantitative assessment of the histological lesions showed that rats subjected to I/R developed marked structural damage, whereas significantly less tubular damage was observed in the EPO-treated group. I/R caused an increase in TUNEL-positive cells that was accompanied by morphological evidence of apoptosis. In the EPO-treated rats only a few scattered TUNEL-positive cells were observed. Up-regulation of Bax in the tubular epithelial cells and increased expression of NF-B was observed in the I/R-treated rats, while diminished expression of Bax and positive immunostaining of NF-B was observed in the EPO-treated rats.
Conclusion. Administration of EPO as a single dose before the onset of ischaemia produced a significant reduction in tubular injury, which was accompanied by a marked amelioration of renal functional impairment. The cytoprotective action of EPO against I/R injury seems to be associated with its anti-apoptotic action. Moreover, transcription factor NF-B is likely to play a pivotal role in the pathophysiology of I/R renal injury and might have a key role in EPO-mediated protective effects.
Keywords: acute renal failure; apoptosis; Bax; erythropoietin; ischaemia/reperfusion damage; NF-B; p65
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