Inhibition of gap junction composed of Cx43 prevents against acute kidney injury following liver transplantation

Dongdong Yuan,Xiaoyun Li,Chaojin Chen,Rongzong Qiu,Nan Cheng,Xianlong Li,Haocong Ji,Ziqing Hei,Gangjian Luo,Chenfang Luo

doi:10.1038/s41419-019-1998-y

Abstract

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.

Highlights

Liver transplantation (LT) is the most effective therapy for patients with end-stage liver disease[1]
It had been reported that Cx43 inhibition protected the brain or myocardium against I/R injuries through attenuating oxidative stress and cell apoptosis[12,13], and death signal transduction mediated by Cx43 could lead to the continuous expansion of injury[14], which prompts us that Gap junctions (GJs) composed of Cx43 mediating the direct molecules transfer between the neighboring cells might be responsible for the renal damage deterioration and magnification
Patients receiving LT experienced prolonged hypotension and serious endotoxemia As illustrated in Fig. 1b, patients with postoperative acute kidney injury (AKI) experienced prolonged hypotension when the inferior vena cava and portal vein were clamped during operation, and the Mean arterial pressure (MAP) did not recover to the baseline value until 30 min after vascular unclamping

Summary

Introduction

Liver transplantation (LT) is the most effective therapy for patients with end-stage liver disease[1]. Yuan et al Cell Death and Disease (2019)10:767 hypoperfusion-induced ischemia–reperfusion (I/R) injury, while intestinal congestion leads to endotoxin production[5,6]. These events increase the risk of renal, oxidative, and inflammatory injury. It had been reported that Cx43 inhibition protected the brain or myocardium against I/R injuries through attenuating oxidative stress and cell apoptosis[12,13], and death signal transduction mediated by Cx43 could lead to the continuous expansion of injury[14], which prompts us that GJ composed of Cx43 mediating the direct molecules transfer between the neighboring cells might be responsible for the renal damage deterioration and magnification

Methods

Results

Conclusion