DsbA‐L deletion attenuates LPS‐induced acute kidney injury by modulating macrophage polarization

Abstract

AbstractDisulfide bond A oxidoreductase‐like protein (DsbA‐L) drives acute kidney injury (AKI) by directly upregulating the expression of voltage‐dependent anion‐selective channels in proximal tubular cells. However, the role of DsbA‐L in immune cells remains unclear. In this study, we used an LPS‐induced AKI mouse model to assess the hypothesis that DsbA‐L deletion attenuates LPS‐induced AKI and explore the potential mechanism of DsbA‐L action. After 24 hours of LPS exposure, the DsbA‐L knockout group exhibited lower serum creatinine levels compared to the WT group. Furthermore, peripheral levels of the inflammatory cytokine IL‐6 were decreased. Transcriptomic data analysis revealed a significant down‐regulation in the IL‐17 and tumor necrosis factor pathways in DsbA‐L knockout mice following LPS induction. Metabolomic analysis suggested that arginine metabolism was significantly different between the WT and DsbA‐L knockout groups after LPS treatment. Notably, the M1 polarization of macrophages in the kidneys of DsbA‐L knockout AKI mice was significantly reduced. Expression of the transcription factors NF‐κB and AP‐1 was downregulated after DsbA‐L knockout. Our results suggest that DsbA‐L regulates LPS‐mediated oxidative stress, promotes M1 polarization of macrophages, and induces expression of inflammatory factors via the NF‐κB/AP‐1 pathway.