RESUMO
Erythropoietin (EPO) has been linked to cardioprotective effects. However, its effects during the aging process are little known. We investigated the effect of EPO administration on hemodynamic parameters, cardiac function, oxidative damage, and erythropoietin receptor (EPOR) expression pattern in the hypovolemic state. EPO was administered (1000 IU/kg/3 days) and then acute hemorrhage (20% blood loss) was induced in young and adult rats. There was no difference in plasmatic EPO in either age group. The hemodynamic basal condition was similar, without alterations in renal function and hematocrit, in both age groups. After bleeding, both EPO-treated age groups had increased blood pressure at the end of the experimental protocol, being greater in adult animals. EPO attenuated the tachycardic effect. Ejection fraction and fractional shortening were higher in adult EPO-treated rats subjected to hemorrhage. In the left ventricle, young and adult EPO-treated rats subjected to bleeding showed an increased EPOR expression. A different EPOR expression pattern was observed in the adult right atrial tissue, compared with young animals. EPO treatment decreased oxidative damage to lipids in both age groups. EPO treatment before acute hemorrhage improves cardiovascular function during the aging process, which is mediated by different EPOR pattern expression in the heart tissue.
Assuntos
Sistema Cardiovascular/efeitos dos fármacos , Epoetina alfa/administração & dosagem , Hematínicos/administração & dosagem , Hemodinâmica/efeitos dos fármacos , Hemorragia/tratamento farmacológico , Função Ventricular Esquerda/efeitos dos fármacos , Fatores Etários , Animais , Sistema Cardiovascular/metabolismo , Sistema Cardiovascular/fisiopatologia , Modelos Animais de Doenças , Hemorragia/metabolismo , Hemorragia/fisiopatologia , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Miocárdio/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Receptores da Eritropoetina/agonistas , Receptores da Eritropoetina/metabolismoRESUMO
It is accepted that osteoblasts/osteocytes are the major source for circulating fibroblast growth factor 23 (FGF23). However, erythropoietic cells of bone marrow also express FGF23. The modulation of FGF23 expression in bone marrow and potential contribution to circulating FGF23 has not been well studied. Moreover, recent studies show that plasma FGF23 may increase early during acute kidney injury (AKI). Erythropoietin, a kidney-derived hormone that targets erythropoietic cells, increases in AKI. Here we tested whether an acute increase of plasma erythropoietin induces FGF23 expression in erythropoietic cells of bone marrow thereby contributing to the increase of circulating FGF23 in AKI. We found that erythroid progenitor cells of bone marrow express FGF23. Erythropoietin increased FGF23 expression in vivo and in bone marrow cell cultures via the homodimeric erythropoietin receptor. In experimental AKI secondary to hemorrhagic shock or sepsis in rodents, there was a rapid increase of plasma erythropoietin, and an induction of bone marrow FGF23 expression together with a rapid increase of circulating FGF23. Blockade of the erythropoietin receptor fully prevented the induction of bone marrow FGF23 and partially suppressed the increase of circulating FGF23. Finally, there was an early increase of both circulating FGF23 and erythropoietin in a cohort of patients with severe sepsis who developed AKI within 48 hours of admission. Thus, increases in plasma erythropoietin and erythropoietin receptor activation are mechanisms implicated in the increase of plasma FGF23 in AKI.