Detection of Hypoxia-Regulated MicroRNAs in Blood as Potential Biomarkers of HIF Stabilizer Molidustat

Background: The recent development of drugs that stabilize HIFalpha, called HIF stabilizers, offers a new strategy for treating anemia. Although these drugs are still in clinical trials, misuse for doping has already begun. Identifying the biomarkers of HIF stabilizers would therefore help in detecting this drug misuse by athletes. Objective: Our aim was twofold: to determine whether hypoxamiRs, the microRNAs associated with the cellular response to hypoxia, are potential biomarkers of HIF stabilizers in blood and whether the response to treatment with an HIF stabilizer differs from the response to a hypoxic environment. Method: Rats were treated for 6 days with either a placebo or 2mg/kg of Molidustat, an HIF stabilizer, or they were put under hypoxia (10% oxygen) for the same length of time. Plasma samples were analyzed before, during and 48 hours after the treatments. Results: EPO concentration increased significantly in plasma during hypoxia and Molidustat treatment and showed a negative retro-control 2 days after the end of the treatments. On the contrary, circulating levels of VEGF were not modified. Among the hypoxamiRs tested, miR-130a and miR-21 were significantly increased during Molidustat treatment and miR-21 was still increased 48 hours after treatment end. Conclusion: Although using these microRNAs as biomarkers seems unlikely due to other possible factors of regulation, this study provides the first identification of a specific effect of HIF stabilizers on microRNAs. Further investigations are needed to better understand the possible consequences of such regulation.