Inhibition of gap junction composed of Cx43 prevents against acute kidney injury following liver transplantation
Inhibition of gap junction composed of Cx43 prevents against acute kidney injury following liver transplantation
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抑制Cx43组成的间隙连接可预防肝移植后急性肾损伤
DOI：
10.1038/s41419-019-1998-y
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发表时间：
2019-10-10
影响因子：
9
通讯作者：
Hei, Ziqing
中科院分区：
文献类型：
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作者：
Yuan, Dongdong;Li, Xiaoyun;Hei, Ziqing
术后急性肾损伤（阿基）是肝移植术后的严重并发症.其恶化和扩大导致死亡率增加。连接蛋白43（Cx43）介导细胞内信号在相邻细胞间的直接传递，一直被认为是器官损伤恶化和扩大的重要生物学基础。因此，我们探讨了Cx43在LT后阿基中的作用及其可能的机制。本研究观察了82例首次原位肝移植患者Cx43表达的变化。我们建立了SD大鼠自体原位肝移植（AOLT）模型和体外肾小管上皮细胞（NRK-52 E）缺氧-复氧（H/R）或脂多糖（LPS）预处理模型，然后采用不同方法改变Cx43通道的功能，观察Cx43通道对LT后阿基的保护作用。结果表明，气管插管时间或重症监护室停留时间较长的阿基患者术后30天和3年的生存率显著较低。在大鼠AOLT模型中，由于庚醇抑制Cx43，术后阿基明显减轻。在体外实验中，用选择性抑制剂或siRNA下调Cx43可保护NRK-52 E细胞免受H/R和/或LPS引起的缺氧后损伤，而上调Cx43则加重上述细胞损伤。值得注意的是，Cx43功能的改变调节了活性氧（ROS）的含量，这不仅有效地介导了氧化应激和炎症反应，而且还调节了坏死性凋亡。因此，我们得出结论，Cx43抑制通过减弱相邻细胞之间的ROS传递来保护LT后的阿基。ROS交替抑制氧化应激和炎症反应，最终减少坏死性凋亡。这可能为LT甚至其他大手术中的器官保护靶向干预提供新的见解。
Postoperative acute kidney injury (AKI) is a severe complication after liver transplantation (LT). Its deterioration and magnification lead to the increase in mortality. Connexin43 (Cx43) mediates direct transmission of intracellular signals between neighboring cells, always considered to be the potent biological basis of organ damage deterioration and magnification. Thus, we explored the effects of Cx43 on AKI following LT and its related possible mechanism. In this study, alternations of Cx43 expression were observed in 82 patients, receiving the first-time orthotopic LT. We built autologous orthotopic liver transplantation (AOLT) models with Sprague–Dawley (SD) rats in vivo, and hypoxia-reoxygenation (H/R) or lipopolysaccharide (LPS) pretreatment models with kidney tubular epithelial cells (NRK-52E) in vitro, both of which were the most important independent risk factors of AKI following LT. Then, different methods were used to alter the function of Cx43 channels to determine its protective effects on AKI. The results indicated that patients with AKI suffering from longer time of tracheal intubation or intensive care unit stay, importantly, had significantly lower survival rate at postoperative 30 days and 3 years. In rat AOLT models, as Cx43 was inhibited with heptanol, postoperative AKI was attenuated significantly. In vitro experiments, downregulation of Cx43 with selective inhibitors, or siRNA protected against post-hypoxic NRK-52E cell injuries caused by H/R and/or LPS, while upregulation of Cx43 exacerbated the above-mentioned cell injuries. Of note, alternation of Cx43 function regulated the content of reactive oxygen species (ROS), which not only mediated oxidative stress and inflammation reactions effectively, but also regulated necroptosis. Therefore, we concluded that Cx43 inhibition protected against AKI following LT through attenuating ROS transmission between the neighboring cells. ROS alternation depressed oxidative stress and inflammation reaction, which ultimately reduced necroptosis. This might offer new insights for targeted intervention for organ protection in LT, or even in other major surgeries.