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.

自噬流降低引发肾小管上皮细胞（renal tubular epithelial cells, RTECs）损伤，是脓毒症相关急性肾损伤（sepsis-associated acute kidney injury, SA-AKI）进展过程中的显著特征。脂多糖（lipopolysaccharide, LPS）刺激可诱导巨噬细胞迁移抑制因子（macrophage migration inhibitory factor, MIF）上调，进而抑制自噬并引发后续细胞损伤。蛋白质组学分析显示，MIF与高迁移率族蛋白B1（High Mobility Group Box 1, HMGB1）的相互作用对自噬激活具有调控作用。对肾脏特异性Mif基因条件性敲除（CKO-Mif）小鼠的研究表明，肾小管上皮细胞中的MIF可干扰自噬过程，最终导致肾小管上皮细胞损伤与肾功能障碍。研究发现，MIF通过干扰核心结合位点，抑制HMGB1与Beclin1之间的相互作用。值得注意的是，抑制HMGB1可逆转CKO-Mif小鼠中观察到的异常效应。此外，包含核心结合位点的HMGB1肽段经体内分段筛选与鉴定后，可拮抗MIF介导的自噬抑制，从而减轻肾小管上皮细胞损伤并维持肾功能。该HMGB1肽段能够增强自噬激活，对肾小管上皮细胞及肾功能具有保护作用。本研究阐明了MIF调控自噬的具体机制，为脓毒症相关急性肾损伤的治疗提供了全新策略。