Erythropoietin and carbamylated-erythropoietin effects upon neuronal and erythropoietic systems. Mechanisms and receptors involved

CHAMORRO MARÍA EUGENIA; WENKER SHIRLEY; VOTA DAIANA; VITTORI DANIELA; NESSE, ALCIRA

Florencia

Congreso; 8th World Congress of IBRO (International Brain Research Organization); 2011

International Brain Research Organization

In addition to its hematopoietic function, erythropoietin (Epo) has also neuroprotective properties. Since erythropoiesis stimulation is unwanted for neuroprotection, Epo-like compounds with more selective action are under investigation. One such compound, the carbamylated erythropoietin (cEpo), experimentally has demonstrated non-hematopoietic tissue protection without erythropoietic effect. Since little is known about cellular mechanisms which could explain the action of cEpo, our aim was to compare Epo and cEpo activities. Both erythropoietins were alike to prevent apoptosis induced by either staurosporine or TNF-alpha in neuronal SH-SY5Y cells by mechanisms mediated by PI3K and Jak2 signalling pathways. Different from Epo, cEpo did not act as growth factor in the development of mice CFU-E or in cultures of UT-7 and TF-1 cells, and did nor prevent TNF-induced apoptosis of erythroid differentiated K562 cells. To investigate whether cEpo would be able to interfere with Epo erythropoietic action, competitive assays were performed. Interestingly, high cEpo/Epo ratio added simultaneously to cultures completely prevented CFU-E growth, although this inhibition disappeared when cEpo was added after stimulation by Epo. Provided that two different receptors, the homodimeric EpoR-EpoR and the heterodimeric EpoR-beta common (bc), may be involved in the action of Epo and cEpo, we investigated possible modulation of both receptors in erythroid and neuronal cells. The EpoR as well as the bc subunit were found expressed in undifferentiated neuronal SH-SY5Y cells and in cells with erythroid differentiation ability (UT-7 and TF-1). Moreover, both receptors were modulated by Epo or cEpo in neuronal cells. In UT-7 cells, EpoR expression was regulated by Epo whereas cEpo modulated bc expression. Results clearly demonstrate differential action of Epo and cEpo in neuronal and erythroid cells. Even though mediation of two receptors in different tissues may explain Epo and cEpo effects, the interference of cEpo with Epo still introduce a question in this concern.