Erythropoietin induces miRNA‐210 by JAK2/STAT5 signaling in PBMCs of End‐stage Renal Disease patients

Abstract

Anemia of Chronic Kidney Disease is associated with blunted response/resistance to Erythropoietin Stimulating Agents (ESA) in hemodialysis patients (HD). Several molecules have been successful associated to ESA‐responsiveness; however, none of them is now considered a valid therapeutic biomarker of Erythropoietin resistance in these patients. We performed evaluation of the level of specific plasma circulating miRNAs in blood samples of HD, in relation to ESA treatment, with a follow up of one year (T0‐T3). We found significant lower circulating levels of all miRNAs analyzed at baseline (T0) in HD patients vs. Healthy Control (HC). The plasmatic levels of miRNA210 resulted significantly and negatively associated to Erythropoietin Resistance Index (ERI), and the variance of ΔmiRNA210 (miRNA210_T3 minus miRNA210_T0) explained significant percentage of ΔERI (ERI_T3 minus ERI_T0) variance. The Receiver Operating Characteristic analysis at T0, showed that the plasmatic level of miRNA210 could distinguish HD patients with positive or negative trend in ERI at T3. In vitro, recombinant human EPO induced significant release of miRNA210 from cultured PBMCs, through the activation of JAK2/STAT5 signaling, but not by the activation of the MAPK p38α and ERK1/2. In accordance, HD patients with negative ΔERI, showed higher level of p‐JAK2, and nuclear translocation of p‐STAT5 vs. patients with positive ΔERI or HC. Our data highlighted that chronic HD significantly reduces the circulating level of the miRNAs evaluated; within the targets analyzed, the miRNA210 could be considered a prognostic indicator of ESA responsiveness and index for anemia management.