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.
Bibliographical noteFunding Information:
We thank Andrés Stutzin, Aquíles Jara, and Antonello Penna for helpful advice and Eliana Pino for general technical assistance. This work was supported by FONDECYT Regular grants 1130550, 1171869 (LM), and 1151423 (RA), CONICYT PhD scholarship 21120552 DN 2012 (AG-I). The Millennium Nucleus of Ion Channels-Associated Diseases (MiNICAD) and the Millennium Institute on Immunology and Immunotherapy P09/016-F(ICM) are supported by the Iniciativa Científica Milenio of the Ministry of Economy, Development and Tourism (Chile).
© 2017 International Society of Nephrology
- acute kidney injury