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Abstract: Donors with a serum sodium concentration of >155 mmol/L are extended criteria donors for liver transplantation (LT). Elevated serum sodium of donors leads to an increased incidence of hepatic dysfunction in the early postoperative period of LT; however, the exact mechanism has not been reported. We constructed a Lewis rat model of 70% hepatic parenchymal area subjected to ischemia-reperfusion (I/R) with hypernatremia and a BRL-3A cell model of hypoxia-reoxygenation (H/R) with high-sodium (HS) culture medium precondition. To determine the degree of injury, biochemical analysis, histological analysis, and oxidative stress and apoptosis detection were performed. We applied specific inhibitors of the epithelial sodium channel (ENaC) and na⁺/Ca²⁺ exchanger (NCX) in vivo and in vitro to verify their roles in injury. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) levels and the area of hepatic necrosis were significantly elevated in the HS+I/R group. Increased reactive oxygen species (ROS) production, myeloperoxidase (MPO)‍-positive cells, and aggravated cellular apoptosis were detected in the HS+I/R group. The HS+H/R group of BRL-3A cells showed significantly increased cellular apoptosis and ROS production compared to the H/R group. The application of amiloride (Amil), a specific inhibitor of ENaC, reduced ischemia-reperfusion injury (IRI) aggravated by HS both in vivo and in vitro, as evidenced by decreased serum transaminases, inflammatory cytokines, apoptosis, and oxidative stress. SN-6, a specific inhibitor of NCX, had a similar effect to Amil. In summary, hypernatremia aggravates hepatic IRI, which can be attenuated by pharmacological inhibition of ENaC or NCX.

药物抑制ENaC或NCX可减轻高钠血症加重的肝脏缺血再灌注损伤

[1]BasmajiJ,HornbyL,RochwergB,et al.,2020.Impact of donor sodium levels on clinical outcomes in liver transplant recipients: a systematic review.Eur J Gastroenterol Hepatol,32(12):1489-1496.

[2]Bastos-NevesD,SalvalaggioPRO,AlmeidaMD,2019.Risk factors, surgical complications and graft survival in liver transplant recipients with early allograft dysfunction.Hepatobiliary Pancreat Dis Int,18(5):423-429.

[3]BernalA,ZafraMA,SimónMJ,et al.,2023.Sodium homeostasis, a balance necessary for life.Nutrients,15(2):395.

[4]CastaldoP,MacriML,LaricciaV,et al.,2017.Na⁺/Ca²⁺ exchanger 1 inhibition abolishes ischemic tolerance induced by ischemic preconditioning in different cardiac models.Eur J Pharmacol,794:246-256.

[5]CeresaCDL,NasrallaD,PollokJM,et al.,2022.Machine perfusion of the liver: applications in transplantation and beyond.Nat Rev Gastroenterol Hepatol,19(3):199-209.

[6]ChenQB,LiQ,LiangYQ,et al.,2022.Natural exosome-like nanovesicles from edible tea flowers suppress metastatic breast cancervia ROS generation and microbiota modulation.Acta Pharm Sin B,12(2):907-923.

[7]ChenSY,ZhangHP,LiJ,et al.,2021.Tripartite motif-containing 27 attenuates liver ischemia/reperfusion injury by suppressing transforming growth factor β‍-activated kinase 1 (TAK1) by TAK1 binding protein 2/3 degradation. Hepatology,73(2):738-758.

[8]ChenYB,YuX,YanZP,et al.,2023.Role of epithelial sodium channel-related inflammation in human diseases.Front Immunol,14:1178410.

[9]DarWA,SullivanE,BynonJS,et al.,2019.Ischaemia reperfusion injury in liver transplantation: cellular and molecular mechanisms.Liver Int,39(5):788-801.

[10]DingMJ,FangHR,ZhangJK,et al.,2022.E3 ubiquitin ligase ring finger protein 5 protects against hepatic ischemia reperfusion injury by mediating phosphoglycerate mutase family member 5 ubiquitination.Hepatology,76(1):94-111.

[11]DizinE,OlivierV,RothI,et al.,2021.Activation of the hypoxia-inducible factor pathway inhibits epithelial sodium channel-mediated sodium transport in collecting duct principal cells.J Am Soc Nephrol,32(12):3130-3145.

[12]FrindtG,YangL,BambergK,et al.,2018.Na restriction activates epithelial Na channels in rat kidney through two mechanisms and decreases distal Na⁺ delivery.J Physiol,596(16):3585-3602.

[13]GerkauNJ,RakersC,DurryS,et al.,2018.Reverse NCX attenuates cellular sodium loading in metabolically compromised cortex.Cereb Cortex,28(12):4264-4280.

[14]GuoWZ,FangHB,CaoSL,et al.,2020.Six-transmembrane epithelial antigen of the prostate 3 deficiency in hepatocytes protects the liver against ischemia-reperfusion injury by suppressing transforming growth factor-‍β‍-activated kinase 1. Hepatology,71(3):1037-1054.

[15]GuoZY,ZhaoQ,JiaZH,et al.,2023.A randomized-controlled trial of ischemia-free liver transplantation for end-stage liver disease.J Hepatol,79(2):394-402.

[16]HanMJ,LinJ,YangY,et al.,2022.Xinshuaining preparation protects H9c2 cells from H₂O₂-induced oxidative damage through the PI3K/AKt/Nrf-2 signaling pathway.Clin Exp Hypertens,45(1):1-9.

[17]HuHJ,WangSS,WangYX,et al.,2019.Blockade of the forward Na⁺/Ca²⁺ exchanger suppresses the growth of glioblastoma cells through Ca²⁺-mediated cell death.Br J Pharmacol,176(15):2691-2707.

[18]IlardiA,2022.Diagnostic and therapeutic approach to hypernatremia.Diagnosis (Berl),9(4):403-410.

[19]JavidanpourS,DianatM,BadaviM,et al.,2018.The inhibitory effect of rosmarinic acid on overexpression of NCX1 and stretch-induced arrhythmias after acute myocardial infarction in rats.Biomed Pharmacother,102:884-893.

[20]KaltenmeierC,YazdaniHO,HanduS,et al.,2022.The role of neutrophils as a driver in hepatic ischemia-reperfusion injury and cancer growth.Front Immunol,13:887565.

[21]KangBS,ChoiBY,KhoAR,et al.,2020.An inhibitor of the sodium-hydrogen exchanger-1 (NHE-1), amiloride, reduced zinc accumulation and hippocampal neuronal death after ischemia.Int J Mol Sci,21(12):4232.

[22]KingDR,PadgetRL,PerryJ,et al.,2020.Elevated perfusate [Na⁺] increases contractile dysfunction during ischemia and reperfusion.Sci Rep,10:17289.

[23]LiJY,YuDS,HeCH,et al.,2023.KLF6 alleviates hepatic ischemia-reperfusion injury by inhibiting autophagy.Cell Death Dis,14(7):393.

[24]LiY,QuanX,LiXL,et al.,2019.Kdm6A protects against hypoxia-induced cardiomyocyte apoptosis via H3K27me3 demethylation of Ncx gene.J Cardiovasc Transl Res,12(5):488-495.

[25]LinYM,HuangHT,ChenLF,et al.,2023.Assessing donor liver quality and restoring graft function in the era of extended criteria donors.J Clin Transl Hepatol,11(1):219-230.

[26]Lucas-RuizF,MateoSV,Jover-AguilarM,et al.,2023.Danger signals released during cold ischemia storage activate NLRP3 inflammasome in myeloid cells and influence early allograft function in liver transplantation.EBioMedicine,87:104419.

[27]MatsumotoT,DoiS,NakashimaA,et al.,2022.Upregulation of mineralocorticoid receptor contributes to development of salt-sensitive hypertension after ischemia-reperfusion injury in rats.Int J Mol Sci,23(14):7831.

[28]McDonaldMF,BarrettSC,MalikTH,et al.,2021.Elevated serum sodium in recipients of liver transplantation has a substantial impact on outcomes.Transpl Int,34(10):‍1971-1983.

[29]MutchlerSM,HasanM,KohanDE,et al.,2021.Deletion of the gamma subunit of ENaC in endothelial cells does not protect against renal ischemia reperfusion injury.Int J Mol Sci,22(20):10914.

[30]N'GouemoP,2013.Probing the role of the sodium/calcium exchanger in pentylenetetrazole-induced generalized seizures in rats.Brain Res Bull,90:52-57.

[31]PersaudA,JiangC,LiuZT,et al.,2022.Elevated intracellular Na⁺ and osmolarity stimulate catalytic activity of the ubiquitin ligase Nedd4-2.Proc Natl Acad Sci USA,119(30):e2122495119.

[32]PitzerA,ElijovichF,LafferCL,et al.,2022.DC ENaC-dependent inflammasome activation contributes to salt-sensitive hypertension.Circ Res,131(4):328-344.

[33]QuansahH,N'GouemoP,2014.Amiloride and SN-6 suppress audiogenic seizure susceptibility in genetically epilepsy-prone rats.CNS Neurosci Ther,20(9):860-866.

[34]ScamblerT,Jarosz-GriffithsHH,Lara-ReynaS,et al.,2019.ENaC-mediated sodium influx exacerbates NLRP3-dependent inflammation in cystic fibrosis.Elife,8:e49248.

[35]SchlegelA,MuellerM,MullerX,et al.,2023.A multicenter randomized-controlled trial of hypothermic oxygenated perfusion (HOPE) for human liver grafts before transplantation.J Hepatol,78(4):783-793.

[36]ShiXC,YinYJ,GuoXW,et al.,2023.The histone deacetylase inhibitor SAHA exerts a protective effect against myocardial ischemia/reperfusion injury by inhibiting sodium-calcium exchanger.Biochem Biophys Res Commun,671:105-115.

[37]SitbonA,DelmottePR,GoumardC,et al.,2023.Therapeutic potentials of mesenchymal stromal cells-derived extracellular vesicles in liver failure and marginal liver graft rehabilitation: a scoping review.Minerva Anestesiol,89(7-8):690-706.

[38]TarjusA,González-RivasC,Amador-MartínezI,et al.,2019.The absence of endothelial sodium channel α (αENaC) reduces renal ischemia/reperfusion injury.Int J Mol Sci,20(13):3132.

[39]XueJ,ZengWZ,HanY,et al.,2023.Structural mechanisms of the human cardiac sodium-calcium exchanger NCX1.Nat Commun,14:6181.

[40]YuYW,QueJQ,LiuS,et al.,2022.Sodium-glucose co-transporter-2 inhibitor of dapagliflozin attenuates myocardial ischemia/reperfusion injury by limiting NLRP3 inflammasome activation and modulating autophagy.Front Cardiovasc Med,8:768214.

[41]ZhouZJ,ChenGS,SiZZ,et al.,2020.Prognostic factors influencing outcome in adult liver transplantation using hypernatremic organ donation after brain death.Hepatobiliary Pancreat Dis Int,19(4):371-377.