Effects of Roxadustat on HIF-1α and HIF-2α Expression and Hematological Recovery in a Rat Model of Experimental Anemia

Abstract

Background: Roxadustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) that promotes erythropoiesis through stabilization of hypoxia-inducible factors (HIFs). The present study evaluated the effects of Roxadustat on HIF-1α and HIF-2α expression and hematological recovery in experimental anemia.
Objective: In an experimental model of anemia induced by phenylhydrazine, the purpose of this study was to assess the dose-dependent effects of Roxadustat on HIF-1α and HIF-2α expression and hematological recovery.
Methods : Anemia was induced in the subjects through an intraperitoneal (i.p.) injection of phenylhydrazine (PHZ) (40 mg/kg body weight).Two days post-injection, we confirmed the model's success by evaluating hematological parameters, specifically hemoglobin (HGB) levels.The animals were divided into five groups: a healthy control group, an untreated anemia group, and three anemic groups treated orally with Roxadustat at doses of 10, 20, or 40 mg/kg/day for 14 consecutive days. Hematological parameters and the expression levels of HIF-1α and HIF-2α were subsequently evaluated.
Results : When anemia was induced, the RBC count and HCT significantly decreased in comparison to the control group. Hematological parameters were significantly improved by Roxadustat treatment in a dose-dependent manner; the group receiving 40 mg/kg had the highest HCT (48.00 ± 3.10%) and RBC count (7.47 ± 0.50 ×10¹²/L). Additionally, Roxadustat significantly and dose-dependently raised the expression of HIF-1α and HIF-2α. The 40 mg/kg group showed the highest expression levels, with HIF-1α at 4.06 ± 1.98 and HIF-2α at 5.08 ± 1.72. These results show progressive hematological recovery after Roxadustat treatment, along with increased activation of the HIF pathway.In addition ,antioxidant biomarkers including reduced glutathione (GSH) and superoxide dismutase (SOD) showed strong positive correlations with hemoglobin concentration (r = 0.803 and r = 0.819, respectively; p < 0.01).
Conclusion: Roxadustat effectively enhanced hematological recovery and increased HIF-1α and HIF-2α expression in experimental anemia in a dose-dependent manner. The 40 mg/kg dose produced the most pronounced hematological and molecular responses, supporting the role of HIF pathway activation in the erythropoietic effects of Roxadustat.