Erythropoietin Induces miRNA210 by JAK2/STAT5 Signaling in PBMCs of End Stage Renal Disease Patients

Background: Anemia of Chronic Kidney Disease is associated with blunted response/resistance to Erythropoietin Stimulating Agents (ESA) in hemodialysis patients (HD). However, none of the molecules successful associated to ESA-responsiveness is now considered a valid therapeutic biomarker of Erythropoietin resistance. Methods: 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). Findings: We found significant lower circulating levels of all miRNAs analyzed at baseline (T0) in HD vs. Healthy Control (HC). The plasmatic levels of miRNA210 resulted negatively associated to Erythropoietin Resistance Index (ERI), and the variance of ΔmiRNA210 (miRNA210T3 minus miRNA210T0) explained percentage of ΔERI (ERIT3 minus ERIT0) variance. The Receiver Operating Characteristic analysis at T0, showed that miRNA210 could distinguish HD with positive or negative trend in ERI at T3. The recombinant human EPO induced release of miRNA210 from cultured PBMCs, through the activation of JAK2/STAT5 signaling, but no by the activation of the MAPK p38α and ERK1/2. In accordance, HD with negative ΔERI, showed higher level of p-JAK2, and nuclear translocation of p-STAT5 vs. patients with positive ΔERI or HC. Interpretation: The ESA treatment induces expression and release of miRNA210 from PBMCs. The magnitude of this process is negatively associated to ESA resistance. Findings: We highlighted that chronic HD significantly reduces the circulating level of the miRNAs evaluated; within the targets analyzed, the miRNA210 could be considered a plausible prognostic indicator of ESA responsiveness and index for anemia management. Funding Statment: This study was supported by grants from the Ministero dell’Universita e della Ricerca (MIUR). Declaration of Interests: All the authors declared no competing interests. Ethics Approval Statement: The study was approved by the local Ethics Committee (application number E2-02-2015).