MO552PHARMACOLOGICAL HIF PROLYL HYDROXYLASE INHIBITION IMPROVES EXERCISE ENDURANCE CAPACITY IN CKD MICE

Abstract

Abstract Background and Aims Erythropoietin (EPO) and hypoxia-inducible factor (HIF) stabilizers (prolyl hydroxylase (PH) inhibitors) are efficient therapeutic modalities against anemia in chronic kidney disease (CKD). Compared to EPO and EPO receptor system, extra-renal action of PH inhibitors has still not been fully investigated. Previous reports caution us about the actual misuse of PH inhibitors in doped athletes, but the drug nonhematopoietic effects of PH inhibitors on skeletal muscles remain controversial both in healthy subjects or in patients with CKD. Method To study direct pharmacological effects of PH inhibitors on skeletal muscles, one of PH inhibitors, roxadustat, was administered via oral gavage to healthy 8-week-old C57BL6 mice. Plasma EPO levels and HIF-targeted gene expression were analyzed after a single administration. Exercise ability was assessed by treadmill exhaustion test after a single dose or chronic 5-week treatment. Roxadustat was also administered for 2 weeks to CKD mice with 2-week 0.2% adenine diet. Endurance capacity was similarly assessed after 2-week roxadustat treatment. Results Even a single administration of roxadustat increased plasma EPO levels and gene expression downstream of HIF in skeletal muscles. Healthy mice treated with roxadustat for 5 weeks showed higher blood haemoglobin (Hb) levels and improved exercise endurance in treadmill exhaustion test, which was blunted by hemodilution procedure. Adenine-fed CKD mice showed lower blood Hb levels and worse endurance capacity compared to control mice. Roxadustat treatment improved endurance capacity in CKD mice without significant increase in blood Hb levels compared to control mice. Conclusion Treatment with HIF-PH inhibitor, roxadustat, improves exercise endurance principally via pharmacological erythropoiesis. However, roxadustat shows potential effects independent of erythropoiesis on endurance capacity in CKD.