Targeting Macrophage Migration Inhibitory Factor (MIF) in Renal Tubular Epithelial Cells to Restore Autophagy in Sepsis-Associated Acute Kidney Injury

The reduction in autophagic flux, which resulted in injury to renal tubular epithelial cells (RTECs), was a notable characteristic in the progression of sepsis-associated acute kidney injury (SA-AKI). The upregulation of macrophage migration inhibitory factor (MIF) induced by lipopolysaccharide (LPS) stimulation leaded to the inhibition of autophagy and subsequent cellular injury. Proteomic analysis revealed that the interaction between MIF and HMGB1 played a regulatory role in the activation of autophagy. Analysis of the mice with kidney-specific conditional knockout of Mif gene (CKO-Mif) demonstrated that MIF in RTECs interfered with autophagy, consequently causing RTEC injury and renal dysfunction. MIF was found to inhibit the interaction between HMGB1 and Beclin1 by interfering with the core binding sites. Notably, the inhibition of HMGB1 reversed the effects observed in CKO-Mif mice. Moreover, the HMGB1 peptide, containing the core binding sites, was segmented and identified in vivo to counteract MIF-mediated autophagy inhibition, thereby mitigating RTEC injury and preserving renal function. The HMGB1 peptide presented to enhance the autophagy activation and possessed the protective effect to RTECs and renal function. Our study elucidated the mechanism by which MIF regulated autophagy and introduced a novel strategy for the treatment of SA-AKI.