LIGHT aggravates sepsis-associated acute kidney injury via TLR4-MyD88-NF-κB pathway.
LIGHT aggravates sepsis-associated acute kidney injury via TLR4-MyD88-NF-κB pathway.
复制标题
光通过 TLR4-MyD88-NF-κB 通路加重脓毒症相关的急性肾损伤
DOI：
10.1111/jcmm.15815
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发表时间：
2020-10
影响因子：
5.3
通讯作者：
Peng KF
中科院分区：
文献类型：
--
作者：
Zhong Y;Wu S;Yang Y;Li GQ;Meng L;Zheng QY;Li Y;Xu GL;Zhang KQ;Peng KF
脓毒症相关急性肾损伤（阿基）是一种常见的临床重症监护综合征。由于其高发病率和高死亡率而受到越来越多的关注;然而，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，是一种调节炎症的双向免疫调节分子，在疾病发病机制中起着关键作用。在本研究中，腹腔注射LPS的小鼠和用LPS攻击的HK-2细胞分别用作体内和体外阿基模型。LIGHT缺乏可明显减轻肾脏病理损伤和肾功能损害，并通过减少体内炎症介质的产生和炎性细胞浸润，明显减轻炎症反应。与对照组相比，LIGHT敲除小鼠肾脏中的TLR 4-Myd 88-NF-κB信号通路显著下调。重组人LIGHT通过上调TLR 4-Myd 88-NF-κB信号通路的表达和炎症水平加重LPS处理的HK-2细胞损伤。TAK 242（选择性TLR 4抑制剂）在一定程度上降低了这一趋势。此外，在小鼠中用可溶性受体融合蛋白HVEM-Fc或LTβ R-Fc阻断LIGHT可减轻阿基的肾功能障碍和病理损伤。我们的研究结果表明，LIGHT通过TLR 4-Myd 88-NF-κB信号通路减轻炎症并促进LPS诱导的阿基的肾脏损伤，这为治疗阿基提供了潜在的策略。
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.
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影响因子：
158.5
作者：
MICHIE, HR;MANOGUE, KR;WILMORE, DW
通讯作者：
WILMORE, DW
DOI：
10.1124/jpet.114.221085
发表时间：
2015-02-01
影响因子：
3.5
作者：
Smith, Joshua A.;Stallons, L. Jay;Schnellmann, Rick G.
通讯作者：
Schnellmann, Rick G.
影响因子：
4.4
作者：
Cunningham, PN;Wang, Y;Quigg, RJ
通讯作者：
Quigg, RJ
影响因子：
4.8
作者：
Harrop, JA;McDonnell, PC;Young, PR
通讯作者：
Young, PR
影响因子：
3.3
作者：
Gómez H;Kellum JA
通讯作者：
Kellum JA