Transcriptional regulation of endothelin-1 by erythropoietin in endothelial cells.

Recombinant human erythropoietin (rHuEpo) has been widely used in patients undergoing chronic hemodialysis treatment to correct anemia. In a subgroup of patients, i.v. administration of rHuEpo leads to manifestation or worsening of hypertension. The underlying mechanism of this remains unclear but it has been suggested that it is associated with increased expression of the vasoconstrictor endothelin (ET) in endothelial cells (ECs). There is also evidence for expression of specific rHuEpo receptors on ECs. The aim of this work was to study the time course and mechanisms of ET-1 regulation on the mRNA level in bovine aortic endothelial cells (BAECs) and human umbilical vein endothelial cells (HUVECs) stimulated with pharmacologic doses of rHuEpo (1-10 IU/ml). Compared to vehicle-treated controls, rHuEpo-treatment of ECs increases preproET-1 mRNA expression up to 170%, as shown by Northern blotting. To study the transcriptional regulation of ET-1 expression by rHuEpo, ECs were transfected with a luciferase construct driven by the rat ET-1 promoter and subsequently stimulated with rHuEpo. Compared to controls, luciferase activity increased up to 200% (n = 6; p < 0.05), suggesting transcriptional regulation of preproET-1 mRNA-expression by rHuEpo. Our data support the hypothesis that ET contributes to the hypertensive side effects of rHuEpo treatment and that this interaction occurs at the transcriptional level.