Department of Anesthesiology, the third affiliated Hospital of Sun Yat-sen University, Tianhe Road, Guangzhou, PR China.
Department of Anesthesiology, Huizhou first People's Hospital, No. 20, San Xin Nan Road, Jiangbei, Huizhou, PR China.
Cell Death Dis. 2019 Oct 10;10(10):767. doi: 10.1038/s41419-019-1998-y.
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.
术后急性肾损伤（AKI）是肝移植（LT）后的严重并发症。其恶化和放大导致死亡率增加。连接蛋白 43（Cx43）介导相邻细胞之间的细胞内信号直接传递，一直被认为是器官损伤恶化和放大的有力生物学基础。因此，我们探讨了 Cx43 在 LT 后 AKI 中的作用及其相关的可能机制。
在这项研究中，观察了 82 名接受首次原位 LT 的患者中 Cx43 表达的变化。我们在体内建立了 Sprague-Dawley（SD）大鼠自体原位肝移植（AOLT）模型，以及体外缺氧再氧合（H/R）或脂多糖（LPS）预处理模型肾肾小管上皮细胞（NRK-52E），这两者都是 LT 后 AKI 的最重要独立危险因素。然后，使用不同的方法改变 Cx43 通道的功能，以确定其对 AKI 的保护作用。
结果表明，AKI 患者需要更长时间的气管插管或重症监护病房停留，重要的是，术后 30 天和 3 年内的生存率明显降低。在大鼠 AOLT 模型中，用庚醇抑制 Cx43 后，术后 AKI 明显减轻。体外实验中，用选择性抑制剂或 siRNA 下调 Cx43 可防止 H/R 和/或 LPS 引起的缺氧后 NRK-52E 细胞损伤，而上调 Cx43 则加剧了上述细胞损伤。值得注意的是，Cx43 功能的改变调节了活性氧（ROS）的含量，ROS 不仅有效地介导氧化应激和炎症反应，而且调节坏死性凋亡。因此，我们得出结论，通过减弱相邻细胞之间的 ROS 传递，Cx43 抑制可防止 LT 后 AKI。ROS 的改变抑制了氧化应激和炎症反应，最终减少了坏死性凋亡。这可能为 LT 或其他重大手术中的器官保护提供新的靶点干预思路。
