Abstract Body: Background: Chronic kidney disease (CKD) is a known risk factor for stroke that leads to significant long-term disability. Efferocytosis, the process by which microglia engulf and clear apoptotic cells, is essential for stroke recovery. However, its impairment can hinder recovery and worsen the outcomes. Desidustat, an oral hypoxia-inducible factor-prolyl hydroxylase inhibitor, has emerged as a promising treatment for anemia associated with CKD. Despite its clinical potential, its effects on microglial efferocytosis and subsequent effects on stroke recovery have not yet been studied.

Objective: To evaluate the mechanistic role of desidustat in mitigating CKD-induced defective microglial efferocytosis and enhancing sensorimotor recovery following embolic stroke.

Methods: CKD was induced in adult C57BL/6 mice by oral administration of adenine (50 mg/kg) for 28 days. Acute Ischemic stroke was induced in mice with CKD using an embolic model. Sensorimotor function tests (modified neurological severity score and corner test) were performed for up to 4-weeks post-stroke. Inflammation, apoptosis, and the effect of CKD on microglial efferocytosis following stroke were assessed 72 h post-stroke using in vitro and in vivo functional assays. Desidustat 15 mg/kg was administered orally starting on day 14 of adenine treatment and continued for 28 days post-stroke in mice with CKD. Human-induced microglial cells were used to evaluate the mechanistic role of desidustat in promoting efferocytosis of apoptotic neurons.

Results: Mice with CKD exhibited elevated blood urea nitrogen and creatinine levels, accompanied by tubulointerstitial abnormalities and vascular fibrosis in the kidneys. Stroke induction in mice with CKD resulted in increased cerebral inflammation and reduced microglial efferocytosis 72 h post-stroke which was concomitant with worse neurological outcomes and sensorimotor function tests for up to 4 weeks as compared to controls. Desidustat treatment significantly reduced cerebral inflammation and enhanced microglial efferocytosis (72 h post-stroke) and improved neurological recovery and sensorimotor function for up to 4 weeks. In vitro mechanistic studies revealed that desidustat directly enhanced efferocytosis in a human microglial-neuronal co-culture assay.

Conclusion: Our results demonstrated that desidustat treatment enhances microglial efferocytosis and improves neurological outcomes and sensorimotor deficits following ischemic stroke in mice.