Hypertension induced by erythropoietin has a correlation with truncated erythropoietin receptor mRNA in endothelial progenitor cells of hemodialysis patients.
Endothelial nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) contribute to erythropoietin (EPO)-induced hypertension, a major adverse reaction associated with EPO therapy. To investigate the mechanism of EPO-induced hypertension, we examined circulating endothelial progenitor cells (EPCs) taken from 56 hemodialysis (HD) patients. Among these EPCs (which reflect the condition of the endothelium), we looked for EPO receptor (EPOR) mRNAs. A truncated form of EPOR acts as a dominant negative regulator of EPO signaling, leading to hypertension. We found that the ratio of truncated EPOR mRNA in EPCs has a correlation with EPO-induced increase in blood pressure (r = 0.36, P = 0.02). The ratio of truncated to total EPOR mRNA in EPCs had an inverse correlation with EPO-induced cGMP production in vitro (r = -0.31, P = 0.02). A similar correlation was observed in cultured human endothelial cells after transfection of the full-length or truncated forms of EPOR (r = -0.92, P < 0.001). It follows, therefore, that evaluation of EPOR isoform mRNA in EPCs can predict EPO-induced hypertension. The termination of the EPO signal by truncated EPORs may decrease NO/cGMP production after EPO exposure, thereby raising blood pressure.
Ioka
T
T
Department of Nephrology, Jichi Medical University, Tochigi, Japan.
Tsuruoka
S
S
Ito
C
C
Iwaguro
H
H
Asahara
T
T
Fujimura
A
A
Kusano
E
E
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000740:Anemia / Q000188:drug therapy* / Q000209:etiology; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism*; D004921:Erythropoietin / Q000008:administration & dosage / Q000009:adverse effects*; D005260:Female; D006801:Humans; D006973:Hypertension / Q000139:chemically induced* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009569:Nitric Oxide / Q000378:metabolism; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism*; D017467:Receptors, Erythropoietin / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins; D006435:Renal Dialysis / Q000009:adverse effects*; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism*; D014162:Transfection; D015854:Up-Regulation
D018076:DNA, Complementary; D012333:RNA, Messenger; D017467:Receptors, Erythropoietin; D011994:Recombinant Proteins; D004921:Erythropoietin; D009569:Nitric Oxide; D006152:Cyclic GMP