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

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.

Andrade-Oliveira Salvianolic Acid B Modulates Caspase-1–Mediated Pyroptosis in Renal Ischemia-Reperfusion Injury via Nrf2 Pathway

“…for 24 h; Positive control group: cells were incubated in certain concentration of NLRP3 inhibitor MCC950(S7809;Selleck), caspase-1 specific inhibitor VX-765(S2228;Selleck) for 2 h, and were then placed in a hypoxia incubator chamber (27310, stemcell) hypoxia (5% CO2, 95% N2) for 6 h and then reoxygenated for an additional 1 h (5% CO2, 21% O2, 74% N2). The model establishment was decided according to the previous studies ( Liu et al, 2019 ; Yuan et al, 2019 ).…”

Dexmedetomidine Attenuates LPS-Induced Monocyte-Endothelial Adherence via Inhibiting Cx43/PKC-α/NOX2/ROS Signaling Pathway in Monocytes

“…As a transmembrane protein, it has been reported that the carboxyl-terminal domain of Cx43 can interact with some cellular signaling pathways, the most important one of which is just PKC [ 10 , 12 ]. This kind of interaction provides the possibility that Cx43 expression on cell membrane can influence other signaling pathways in cytoplasm.…”

“…The expressions of VLA-4, LFA-1, NOX2, PKC- α , and Cx43 are detected by western blotting, followed the standard procedures as described [ 12 ]. Briefly, U937 monocytes are washed with cold PBS twice and harvested in lysis buffer (Bio-Rad, Hercules, CA), sonicated, and centrifuged for 30 min at 4°C.…”

“…According to the analysis of the transmembrane structure of Cx43 protein, we notice that its carboxyl-terminal domain can interact with some cellular signaling pathways, the most important one of which is just PKC. PKC activation has been identified to play an important part in inflammation and oxidative stress [12]. This kind of interaction provides the possibility that Cx43 expression on cell membrane influences other signaling pathways in cytoplasm.…”

Development and Performance Assessment of Novel Machine Learning Models to Predict Pneumonia After Liver Transplantation

“…The grafts were procured from either donation of circulatory death (DCD), donation of brain death (DBD) or living donors, with standardized techniques in accordance with the guidelines implemented by Chinese Medical Association. The standard implantation technique in our center was piggy back cava anastomosis as we reported previously (19). Preoperative dialysis or preoperative continuous blood puri cation (CBP) were adopted for patients with preoperative renal injury.…”