单宁酸通过抑制铁死亡改善小鼠肾脏缺血-再灌注损伤  

Tannic acid alleviates renal ischemia-reperfusion injury in mice by inhibiting ferroptosis

作　　者：王晓[1] 刘东 庄锦炀 黎忠大 李毅[2] 申升 Wang Xiao;Liu Dong;Zhuang Jinyang;Li Zhongda;Li Yi;Shen Sheng(Department of Organ Transplantation,Guangdong Second Provincial General Hospital Affiliated to Jinan University,Guangzhou 510317,China;不详)

机构地区：[1]暨南大学附属广东省第二人民医院器官移植科,广州510317 [2]中南大学湘雅医院呼吸与危重症医学科

出　　处：《器官移植》2024年第6期912-919,共8页Organ Transplantation

基　　金：国家自然科学青年科学基金项目(82000089)。

摘　　要：目的探索单宁酸在小鼠肾脏缺血-再灌注损伤(IRI)中的作用及机制。方法雄性C57BL/6J小鼠随机分为假手术组(Sham组)、空白对照组(Sham+TA组)、实验组(IRI组)和治疗组(IRI+TA组),每组20只。观察肾脏IRI术后48 h小鼠生存情况。IRI 24 h后留取小鼠血清和肾组织标本(每组各5只),检测小鼠血尿素氮与血清肌酐水平。检测肾组织炎症因子及铁死亡相关指标水平;评估肾脏组织病理损伤。检测肾组织谷胱甘肽过氧化物酶4(GPX4)、酰基辅酶A合成酶长链家族4(ACSL4)蛋白表达水平。使用分子对接软件探究单宁酸与核因子E2相关因子2(Nrf2)结合活性,并验证Nrf2、血红素加氧酶-1(HO-1)表达。结果与IRI组相比,IRI+TA组小鼠术后生存率较高(0比60%),血清肌酐、血尿素氮水平下降,肾组织白细胞介素(IL)-6、IL-1β、肿瘤坏死因子(TNF)-α水平下降,肾组织损伤改善,肾组织丙二醛、亚铁离子水平降低,谷胱甘肽水平升高,GPX4表达增多,ACSL4表达减少(均为P<0.05)。单宁酸可与Nrf2形成合适的空间互补,其结合能为−8.7 kcal/mol,单宁酸与Nrf2具有较强的结合能力。IRI+TA组小鼠肾组织中Nrf2、HO-1蛋白水平上调。结论单宁酸可能与Nrf2蛋白结合,激活Nrf2/HO-1通路抑制铁死亡,改善小鼠肾脏IRI。Objective To explore the role and mechanism of tannic acid in renal ischemia-reperfusion injury(IRI)in mice.Methods Male C57BL/6J mice were randomly divided into sham operation group(Sham group),blank controlgroup(Sham+TA group),experimental group(IRI group)and treatment group(IRI+TA group),with 20 mice in eachgroup.The survival of mice after renal IRI was observed 48 h after surgery.Serum and renal tissue samples were collectedfrom mice 24 h after IRI(5 mice per group),and the levels of blood urea nitrogen and serum creatinine were detected.Thelevels of inflammatory factors and ferroptosis-related indicators in renal tissue were detected.The pathological damage ofrenal tissue was assessed.The protein expression levels of glutathione peroxidase 4(GPX4)and acyl-CoA synthetase long-chain family 4(ACSL4)in renal tissue were detected.Molecular docking software was used to explore the binding activityof tannic acid with nuclear factor E2-related factor 2(Nrf2)and to verify the expression of Nrf2 and heme oxygenase-1(HO-1).Results Compared with the IRI group,the postoperative survival rate of mice in the IRI+TA group was higher(0vs.60%),the levels of serum creatinine and blood urea nitrogen were decreased,the levels of interleukin(IL)-6,IL-1β,andtumor necrosis factor(TNF)-αin renal tissue were decreased,the renal tissue injury was improved,the levels ofmalondialdehyde and ferrous ions in renal tissue were reduced,the level of glutathione was increased,the expressionof GPX4 was increased,and the expression of ACSL4 was decreased(all P<0.05).Tannic acid may form a suitablespatial complement with Nrf2,with a binding energy of−8.7 kcal/mol,indicating a strong binding ability of tannic acidwith Nrf2.The protein levels of Nrf2 and HO-1 in the renal tissue of mice in the IRI+TA group were upregulated.Conclusions Tannic acid may bind to Nrf2 protein,activate the Nrf2/HO-1 pathway to inhibit ferroptosis,and alleviaterenal IRI in mice.

关 键 词：单宁酸 肾移植 缺血-再灌注损伤 铁死亡 核因子E2相关因子2 血红素加氧酶-1 炎症因子 分子对接 

分 类 号：R617[医药卫生—外科学] R692[医药卫生—临床医学]