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      Erythropoietin in Experimental Acute Renal Failure


      Cardiorenal Medicine

      S. Karger AG

      Animal model, Erythropoietin, Apoptosis, Acute renal failure

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          The haematopoietic factor erythropoietin (EPO) has recently been recognized to play a physiological role in the brain and other tissues. The EPO receptor is present in the glomerulus, mesangial and tubular epithelial cells in the kidney. We have reviewed the experimental use of EPO in animal models of acute renal failure. EPO attenuates the dysfunction and histological changes associated with ischaemia-reperfusion injury, with a reduction in apoptotic cell death. EPO has also shown benefit in animal models of systemic shock and cisplatin-induced nephrotoxicity. In vitro studies have shown that EPO has direct effects on proliferation and cell death in proximal tubular epithelial cells. There is increasingly strong experimental evidence that EPO may be of therapeutic use in acute renal failure, and clinical trials should be undertaken to determine its clinical applications in this field.

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          Most cited references 14

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          Derivatives of erythropoietin that are tissue protective but not erythropoietic.

          Erythropoietin (EPO) is both hematopoietic and tissue protective, putatively through interaction with different receptors. We generated receptor subtype-selective ligands allowing the separation of EPO's bioactivities at the cellular level and in animals. Carbamylated EPO (CEPO) or certain EPO mutants did not bind to the classical EPO receptor (EPOR) and did not show any hematopoietic activity in human cell signaling assays or upon chronic dosing in different animal species. Nevertheless, CEPO and various nonhematopoietic mutants were cytoprotective in vitro and conferred neuroprotection against stroke, spinal cord compression, diabetic neuropathy, and experimental autoimmune encephalomyelitis at a potency and efficacy comparable to EPO.
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            Erythropoietin protects the kidney against the injury and dysfunction caused by ischemia-reperfusion.

            Erythropoietin (EPO) is upregulated by hypoxia and causes proliferation and differentiation of erythroid progenitors in the bone marrow through inhibition of apoptosis. EPO receptors are expressed in many tissues, including the kidney. Here it is shown that a single systemic administration of EPO either preischemia or just before reperfusion prevents ischemia-reperfusion injury in the rat kidney. Specifically, EPO (300 U/kg) reduced glomerular dysfunction and tubular injury (biochemical and histologic assessment) and prevented caspase-3, -8, and -9 activation in vivo and reduced apoptotic cell death. In human (HK-2) proximal tubule epithelial cells, EPO attenuated cell death in response to oxidative stress and serum starvation. EPO reduced DNA fragmentation and prevented caspase-3 activation, with upregulation of Bcl-X(L) and XIAP. The antiapoptotic effects of EPO were dependent on JAK2 signaling and the phosphorylation of Akt by phosphatidylinositol 3-kinase. These findings may have major implications in the treatment of acute renal tubular damage.
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              Erythropoietin regulates endothelial progenitor cells.

              Circulating bone marrow-derived endothelial progenitor cells (EPCs) promote vascular reparative processes and neoangiogenesis, and their number in peripheral blood correlates with endothelial function and cardiovascular risk. We tested the hypothesis that the cytokine erythropoietin (EPO) stimulates EPCs in humans. We studied 11 patients with renal anemia and 4 healthy subjects who received standard doses of recombinant human EPO (rhEPO). Treatment with rhEPO caused a significant mobilization of CD34(+)/CD45(+) circulating progenitor cells in peripheral blood (measured by flow cytometry), and increased the number of functionally active EPCs (measured by in vitro assay) in patients (week 2, 312% +/- 31%; week 8, 308% +/- 40%; both P <.01 versus baseline) as well as in healthy subjects (week 8, 194% +/- 15%; P <.05 versus baseline). The effect on EPCs was already observed with an rhEPO dose of about 30 IU/kg per week. Administration of rhEPO increased the number of functionally active EPCs by differentiation in vitro in a dose-dependent manner, assessed in cell culture and by tube formation assay. Furthermore, rhEPO activates the Akt protein kinase pathway in EPCs. Erythropoietin increases the number of functionally active EPCs in humans. Administration of rhEPO or EPO analogs may open new therapeutic strategies in regenerative cardiovascular medicine.

                Author and article information

                Nephron Exp Nephrol
                Cardiorenal Medicine
                S. Karger AG
                October 2006
                14 July 2006
                : 104
                : 3
                : e83-e88
                William Harvey Research Institute, Queen Mary College, University of London, London, UK
                94546 Nephron Exp Nephrol 2006;104:e83–e88
                © 2006 S. Karger AG, Basel

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                Page count
                Figures: 1, Tables: 1, References: 20, Pages: 1
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                Cardiovascular Medicine, Nephrology

                Acute renal failure, Erythropoietin, Animal model, Apoptosis


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