Sepsis‐associated acute kidney injury (SA‐AKI) is a common clinical critical care syndrome. It has received increasing attention due to its high morbidity and mortality; however, its pathophysiological mechanisms remain elusive. LIGHT, the 14th member of the tumour necrosis factor (TNF) superfamily and a bidirectional immunoregulatory molecule that regulates inflammation, plays a pivotal role in disease pathogenesis. In this study, mice with an intraperitoneal injection of LPS and HK‐2 cells challenged with LPS were employed as a model of SA‐AKI in vivo and in vitro, respectively. LIGHT deficiency notably attenuated kidney injury in pathological damage and renal function and markedly mitigated the inflammatory reaction by decreasing inflammatory mediator production and inflammatory cell infiltration in vivo. The TLR4‐Myd88‐NF‐κB signalling pathway in the kidney of LIGHT knockout mice was dramatically down‐regulated compared to the controls. Recombinant human LIGHT aggravated LPS‐treated HK‐2 cell injury by up‐regulating the expression of the TLR4‐Myd88‐NF‐κB signalling pathway and inflammation levels. TAK 242 (a selective TLR4 inhibitor) reduced this trend to some extent. In addition, blocking LIGHT with soluble receptor fusion proteins HVEM‐Fc or LTβR‐Fc in mice attenuated renal dysfunction and pathological damage in SA‐AKI. Our findings indicate that LIGHT aggravates inflammation and promotes kidney damage in LPS‐induced SA‐AKI via the TLR4‐Myd88‐NF‐κB signalling pathway, which provide potential strategies for the treatment of SA‐AKI.

中文翻译：

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LIGHT通过TLR4-MyD88-NF-κB途径加重了败血症相关的急性肾损伤。

败血症相关的急性肾损伤（SA-AKI）是一种常见的临床危重症候群。由于其高发病率和高死亡率，它受到了越来越多的关注。但是，其病理生理机制仍然难以捉摸。LIGHT是肿瘤坏死因子（TNF）超家族的第14个成员，是调节炎症的双向免疫调节分子，在疾病发病机理中起着关键作用。在这项研究中，腹膜内注射LPS的小鼠和被LPS攻击的HK-2细胞分别用作体内和体外SA-AKI的模型。LIGHT缺乏症通过减少体内炎性介质的产生和炎性细胞浸润显着减轻了肾脏对病理损伤和肾功能的损害，并显着减轻了炎症反应。与对照组相比，LIGHT基因敲除小鼠肾脏中的TLR4-Myd88-NF-κB信号通路显着下调。重组人LIGHT通过上调TLR4-Myd88-NF-κB信号通路的表达和炎症水平来加重LPS治疗的HK-2细胞损伤。TAK 242（一种选择性的TLR4抑制剂）在某种程度上降低了这种趋势。此外，在小鼠中用可溶性受体融合蛋白HVEM-Fc或LTβR-Fc阻断LIGHT可以减轻SA-AKI中的肾功能障碍和病理损害。我们的发现表明，LIGHT通过TLR4-Myd88-NF-κB信号通路加重LPS诱导的SA-AKI中的炎症并促进肾脏损害，这为SA-AKI的治疗提供了潜在的策略。重组人LIGHT通过上调TLR4-Myd88-NF-κB信号通路的表达和炎症水平来加重LPS治疗的HK-2细胞损伤。TAK 242（一种选择性的TLR4抑制剂）在某种程度上降低了这种趋势。此外，在小鼠中用可溶性受体融合蛋白HVEM-Fc或LTβR-Fc阻断LIGHT可以减轻SA-AKI中的肾功能障碍和病理损害。我们的发现表明，LIGHT通过TLR4-Myd88-NF-κB信号通路加重LPS诱导的SA-AKI中的炎症并促进肾脏损害，这为SA-AKI的治疗提供了潜在的策略。重组人LIGHT通过上调TLR4-Myd88-NF-κB信号通路的表达和炎症水平来加重LPS治疗的HK-2细胞损伤。TAK 242（一种选择性的TLR4抑制剂）在某种程度上降低了这种趋势。此外，在小鼠中用可溶性受体融合蛋白HVEM-Fc或LTβR-Fc阻断LIGHT可以减轻SA-AKI中的肾功能障碍和病理损害。我们的发现表明，LIGHT通过TLR4-Myd88-NF-κB信号通路加重LPS诱导的SA-AKI中的炎症并促进肾脏损害，这为SA-AKI的治疗提供了潜在的策略。用可溶性受体融合蛋白HVEM-Fc或LTβR-Fc阻断小鼠的LIGHT可以减轻SA-AKI中的肾功能障碍和病理损害。我们的发现表明，LIGHT通过TLR4-Myd88-NF-κB信号通路加重LPS诱导的SA-AKI中的炎症并促进肾脏损害，这为SA-AKI的治疗提供了潜在的策略。用可溶性受体融合蛋白HVEM-Fc或LTβR-Fc阻断小鼠的LIGHT可以减轻SA-AKI中的肾功能障碍和病理损害。我们的发现表明，LIGHT通过TLR4-Myd88-NF-κB信号通路加重LPS诱导的SA-AKI中的炎症并促进肾脏损害，这为SA-AKI的治疗提供了潜在的策略。