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Perit Dial Int 28(6): 648-654
2008
© 2008 International Society for Peritoneal Dialysis
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Bench

ERYTHROPOIETIN PREVENTS DIALYSIS FLUID-INDUCED APOPTOSIS OF MESOTHELIAL CELLS

Marina Vorobiova ,1, Myriam Malkia,2, Alla Shnaider1, Ana Basok1, Boris Rogachev1, Eli C. Lewis2, Cidio Chaimovitz1, Moshe Zlotnik1 and Amos Douvdevani1,2

Departments of Nephrology1 and Clinical Biochemistry,2 Soroka Medical University Center and Ben-Gurion University of the Negev, Beer-Sheva, Israel

Footnotes

a Authors Vorobiov and Malki contributed equally to this mauscript.

Correspondence to: A. Douvdevani, Nephrology Laboratory, Soroka Medical Center, PO Box 151, Beer-Sheva, 84101, Israel. amosd{at}bgu.ac.il

{diamondsuit} Background: In peritoneal dialysis (PD)-treated patients, denudation of the mesothelium correlates with peritoneal fibrosis and vascular changes. Since recombinant human erythropoietin (rHuEPO) induces a range of cytoprotective cellular responses, rHuEPO treatment may reduce PD fluid (PDF)-induced damage.

{diamondsuit} Methods: To investigate the antiapoptotic effect and mechanism of rHuEPO in peritoneal mesothelial cells (PMCs), isolated mice PMCs were used for in vitro characterization of rHuEPO effects. To confirm the in vitro effects, active caspase-3 was analyzed in imprints of liver visceral peritoneum of mice pretreated overnight with rHuEPO (5000 U/kg intraperitoneally) and exposed to PDF (Dianeal 4.25%; Baxter Healthcare, Deerfield, Illinois, USA) for 4 hours.

{diamondsuit} Results: Mouse PMCs expressed EPO-receptor mRNA and protein. Short exposure to rHuEPO (5 U/mL) induced phosphorylation of JAK2, STAT5, and ERK1/2. PMCs pretreated for 1 hour with rHuEPO showed reduced PDF-induced caspase-3 activation (49.6%) and DNA fragmentation (38.4%) in comparison to cells treated by PDF alone (p < 0.05). rHuEPO treatment induced an increase in ERK1/2 phosphorylation and reduced levels of PDF-induced phospho-P38. PD98059, a specific inhibitor of ERK activation, fully blocked the protective effect of rHuEPO. In mice, rHuEPO reduced the apoptotic effect of PDF, as assessed by the level of active caspase-3.

{diamondsuit} Conclusions: Our study presents new insights into clinical use of rHuEPO in the setting of PD. We found that rHuEPO provides ERK1/2-dependent protection to PMCs from PDF-induced apoptosis. The use of rHuEPO, or any of its new derivatives that do not stimulate erythropoiesis, should be considered for peritoneal preservation.

KEY WORDS: Apoptosis; erythropoietin; erythropoietin signaling; MAP kinases; caspase-3; peritoneal mesothelial cells.

Received 28 January 2008; accepted 28 March 2008.






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