circACTR2 facilitates M1 macrophage activation and exacerbates renal inflammation in mice with chronic kidney disease...

This study elucidates the regulatory role and molecular mechanism of the circular RNA actin-related protein 2 homolog (circACTR2) in macrophage phenotypic transformation and renal injury in chronic kidney disease (CKD). A mouse model of CKD was established via adenine administration. An in vitro inflammatory model was generated using lipopolysaccharide-stimulated RAW264.7 macrophages. Results revealed that circACTR2 expression was significantly elevated in CKD models. Silencing of circACTR2 attenuated renal dysfunction, ameliorated histological injury, and reduced inflammatory cytokines in CKD mice. Silencing of circACTR2 led to a phenotypic change in RAW264.7 cells from M1 type to M2 type. Mechanistic studies in RAW264.7 cells showed that circACTR2 acted as a competing endogenous RNA for microRNA-9-5p (miR-9-5p), thereby relieving repression on runt-related transcription factor 1 (RUNX1). In parallel, circACTR2 stabilized RUNX1 mRNA by interacting with HuR. Functionally, overexpression of RUNX1 or inhibition of miR-9-5p in RAW264.7 cells reversed the protective effects conferred by circACTR2 silencing. In conclusion, circACTR2 exacerbates renal inflammation and injury in CKD by promoting M1 macrophage polarization via the miR-9-5p/HuR/RUNX1 axis.