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Inhibition of Erythrocyte Cation Channels by Erythropoietin

Svetlana Myssina^*, Stephan M. Huber^*, Christina Birka^*, Philipp A. Lang^*, Karl S. Lang^*, Björn Friedrich, Teut Risler, Thomas Wieder^* and Florian Lang^*

*Department of Physiology, University of Tübingen, and Department of Internal Medicine, University Medical Center, University of Tübingen, Tübingen, Germany.

Correspondence to: Dr. Florian Lang, Physiologisches Institut der Universität Tübingen, Gmelinstr. 5, D-72076 Tübingen, Germany. Phone: +49-7071-29-72194; Fax: +49-7071-29-5618;

ABSTRACT. Recombinant human erythropoietin therapy is used to counteract anemia that is the result of renal insufficiency. It stimulates the formation of peripheral blood erythrocytes by inhibiting apoptosis of erythrocyte precursor cells. Mature erythrocytes have similarly been shown to undergo apoptosis. Hyperosmotic shock and Cl^- removal activate a Ca²⁺-permeable, ethylisopropylamiloride-inhibitable cation channel. The subsequent increase of cytosolic Ca²⁺ activates a scramblase that breaks down cell membrane phosphatidylserine asymmetry, leading to annexin binding. Studied was whether channel activity and erythrocyte cell death are regulated by erythropoietin. Scatchard plot analysis disclosed low-abundance, high-affinity binding of ¹²⁵I-erythropoietin to erythrocytes. Whole cell patch clamp experiments revealed significant inhibition of the ethylisopropylamiloride-sensitive current by 1 U/ml erythropoietin. Cl^- removal triggered annexin binding, an effect abrogated by erythropoietin (1 U/ml) but not by GM-CSF (10 ng/ml). Osmotic shock (700 mOsm) stimulated annexin binding within 24 h in the majority of the erythrocytes, an effect blunted by erythropoietin (1 U/ml) but not by GM-CSF (10 ng/ml). In the nominal absence of Ca²⁺, the effect of osmotic shock was blunted and the effect of erythropoietin abolished. In hemodialysis patients, intravenous administration of erythropoietin (50 IU/kg) within 4 h decreased the number of annexin binding circulating erythrocytes. Erythropoietin binds to erythrocytes and inhibits volume-sensitive erythrocyte cation channels and thus the breakdown of phosphatidylserine asymmetry after activation of this channel. The effect could prolong the erythrocyte lifespan and may contribute to the enhancement of the erythrocyte number during erythropoietin therapy in dialysis patients. E-mail: florian.lang@uni-tuebingen.de

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673