Acute kidney injury (AKI) constitutes a significant public health issue. Sepsis accounts for over 50 % of AKI cases in the ICU. Recent findings from our research indicated that the PRD1-BF1-RIZ1 homeodomain protein 16 (PRDM16) inhibited the progression of diabetic kidney disease (DKD). However, its precise role and regulatory mechanism in sepsis-induced AKI remain obscure. This study reveals that lipopolysaccharide (LPS) and cecum ligation and puncture (CLP) instigated PRDM16 expression in Boston University mouse proximal tubule (BUMPT) cells and mouse kidneys, respectively. Functionally, PRDM16 curtailed LPS-induced ferroptosis. Mechanistically, PRDM16 associates with the promoter regions of nuclear factor-erythroid 2-related factor-2 (NRF2) and augments its expression, subsequently enhancing glutathione peroxidase 4 (GPX4) expression. Additionally, PRDM16 directly engages with the promoter regions of GPX4, stimulating its expression. Notably, these observations were corroborated in human renal tubular epithelial (HK-2) cells. Furthermore, the ablation of PRDM16 from kidney proximal tubules in mice inhibited NRF2 and GPX4 expression, leading to decreased glutathione (GSH)/oxidized glutathione (GSSG) ratio, increased Fe2+ and reactive oxygen species (ROS) production, exacerbated ferroptosis, and AKI progression. Conversely, PRDM16 knock-in exhibited the opposite effects. Ultimately, adenovirus (ADV)-PRDM16 plasmid or poly (lactide-glycolide acid) (PLGA)-encapsulated formononetin not only mitigated sepsis-induced AKI but also alleviated liver, cardiac, and lung injury. In summary, PRDM16 inhibits ferroptosis via the NRF2/GPX4 axis or GPX4 to prevent sepsis-induced multi-organ injury, including AKI. PLGA-encapsulated formononetin presents a promising therapeutic approach.

中文翻译：

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PRDM16 通过靶向 NRF2/GPX4 轴抑制铁死亡，以防止脓毒症相关的急性肾损伤


急性肾损伤 （AKI） 是一个重大的公共卫生问题。脓毒症占 ICU 中 AKI 病例的 50% 以上。我们最近的研究结果表明，PRD1-BF1-RIZ1 同源结构域蛋白 16 （PRDM16） 抑制糖尿病肾病 （DKD） 的进展。然而，它在脓毒症诱导的 AKI 中的确切作用和调节机制仍然不清楚。本研究显示，脂多糖 （LPS） 和盲肠结扎穿刺 （CLP） 分别在波士顿大学小鼠近端小管 （BUMPT） 细胞和小鼠肾脏中诱导 PRDM16 表达。在功能上，PRDM16 减少了 LPS 诱导的铁死亡。从机制上讲，PRDM16 与核因子-红细胞 2 相关因子-2 （NRF2） 的启动子区域结合并增强其表达，随后增强谷胱甘肽过氧化物酶 4 （GPX4） 表达。此外，PRDM16 直接与 GPX4 的启动子区结合，刺激其表达。值得注意的是，这些观察结果在人肾小管上皮 （HK-2） 细胞中得到了证实。此外，小鼠肾近端小管 PRDM16 消融抑制 NRF2 和 GPX4 表达，导致谷胱甘肽 （GSH）/氧化谷胱甘肽 （GSSG） 比率降低，Fe2+ 和活性氧 （ROS） 产生增加，铁死亡加剧和 AKI 进展。相反，PRDM16 敲入表现出相反的效果。最终，腺病毒 （ADV）-PRDM16 质粒或聚（丙交酯-乙交酯酸）（PLGA） 封装的 formononetin 不仅减轻了脓毒症诱导的 AKI，还减轻了肝脏、心脏和肺损伤。总之，PRDM16 通过 NRF2/GPX4 轴或 GPX4 抑制铁死亡，以防止脓毒症诱导的多器官损伤，包括 AKI。PLGA 封装的 formononetin 提供了一种很有前途的治疗方法。