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Tesi etd-07112011-165642

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Tipo di tesi
Tesi di specializzazione
Autore
DA POZZO, ELEONORA
URN
etd-07112011-165642
Titolo
Erythropoietin (EPO) receptor activity: in vitro effects of EPO derivatives.
Struttura
FARMACIA
Corso di studi
BIOCHIMICA CLINICA
Commissione
relatore Dott. Maria Letizia Trincavelli
relatore Prof. Marco Maccheroni
Parole chiave
  • endothelial cells.
  • Erythropoietin receptor
Data inizio appello
2011-07-29
Disponibilità
completa
Riassunto analitico
In endothelial cells, Erythropoietin receptors (EPO-R) mediate the protective, proliferative and angiogenic effects of EPO and its analogues, which act on EPO-R as receptor agonists. Since hormonal receptors are known to undergo functional changes upon chronic exposure to their agonists, and since erythropoiesis stimulating agents (ESAs) are used for the long-term treatment of anemic states, it is crucial to dissect how the responsiveness of these receptors is regulated at vascular level after prolonged exposure to ESAs.
In the present research, we investigated EPO-R desensitization/resensitization in human umbilical vein endothelial cells (HUVEC) upon exposure to three ESAs with different pharmacokinetic profiles: epoetin alpha (EPOα), darbepoetin alpha (DarboEPO) and continuous EPO-R activator (CERA). All these agonists induced the activation of the transcription factor STAT5, the intracellular pathway associated with EPO-R, with monophasic or biphasic kinetics for EPOa/DarboEPO and CERA, respectively. All epoetins induced EPO-R desensitization with a kinetics faster for CERA, with respect to EPOa and DarboEPO. However, recovery of receptor responsiveness was strictly dependent on the type of epoetin, the agonist concentration and the time of exposure to agonist (desensitization time). EPO-R resensitization occurred with faster kinetics after exposure to low epoetins concentrations for a short desensitization time. When the highest concentration of agonists was tested, recovery of receptor responsiveness was faster with CERA with respect to EPOa, and was completely absent with DarboEPO. Our results demonstrate the three ESAs regulate EPO-R resensitization in a highly different way, demonstrating that the type of molecule and the length of EPO-R stimulation are crucial factors in the control of EPO-R function in endothelial cells.
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