C-176 inhibits macrophage polarization towards M1-subtype and ameliorates LPS induced acute kidney injury

Sepsis-induced acute kidney injury (SI-AKI) has become a focal point in nephrology research field due to its high mortality and potential progression to chronic kidney disease (CKD). The increase of M1 macrophages within renal tissue and their associated inflammatory responses are key contributors to renal inflammation and subsequent damage. Additionally, the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling pathway is abnormally activated during the onset of acute kidney injury (AKI). However, the relationship between the activation of this pathway and the increase in M1 macrophages has not been fully elucidated. This study investigated the protective effects and underlying mechanisms of the STING pathway-specific inhibitor C-176 on LPS-induced AKI, using an LPS and IFN-γ induced M1 macrophage model and an LPS-induced sepsis AKI mouse model.

The in vivo results demonstrate that C-176 intervention can alleviate acute kidney injury and improve renal function by reducing macrophage infiltration in renal tissue, decreasing the proportion of M1 macrophages, and mitigating the inflammatory response. Additionally, in vitro results indicate that C-176 intervention inhibits the polarization of M0 macrophages to M1 macrophages, promotes their polarization to M2 macrophages, and reduces the amounts of pro-inflammatory cytokines such as IL-6 and TNF-α at both the protein and gene expression levels. The biological effects of C-176 are associated with the inhibition of STING-IRF3 signaling pathway activation. In summary, the findings of this study have certain scientific significance and application value for exploring the pathogenesis and treatment methods of SI-AKI.