四川大学学报（医学版）2023，Vol.54Issue(6)：1105-1111,7.DOI:10.12182/20231160106
氧化三甲胺通过PI3K/AKT/SREBP1通路诱导肾纤维化
Trimethylamine N-Oxide Induces Renal Fibrosis Through the PI3K/AKT/SREBP1 Pathway
摘要
Abstract
Objective To investigate the role and mechanism of trimethylamine N-oxide(TMAO),a uremic toxin,in renal fibrosis.Methods A total of 20 male BALB/c mice were randomly and evenly assigned to a Control group and a TMAO group.Mice in the Control group received intraperitoneal injection of normal saline,while mice in the TMAO group received intraperitoneal injection of TMAO(20 mg/[kg·d]).The injection was given once a day for 8 weeks.Histopathology and fibrosis of kidney were observed by H&E staining and Masson staining.Immunohistochemistry was performed to determine the levels of alpha smooth muscle actin(α-SMA),recombinant human fibronectin fragment(Fibronectin),and sterol-regulatory element binding protein 1(SREBP1).Western blot was performed to determine α-SMA,SREBP1,phosphatidylinositol 3 kinase(PI3K),phospho-phosphatidylinositol 3 kinase(p-PI3K),protein kinase B(PKB,also known as AKT),and phospho-AKT(p-AKT)protein levels.HK2 cells were treated with SREBP1 small interfering RNA(siRNA)and PI3K/AKT inhibitor,respectively,and the reversal of the effects of TMAO was examined.Results Animal experiments showed that,compared with the Control group,the mice treated with TMAO experienced pathological damage and fibrosis of the kidney tissue and the expression levels of fibrosis markers,α-SMA and Fibronectin,in the kidney were increased(all P＜0.05).According to the findings from further investigation,the TMAO-treatment group showed increased expression of SREBP1 and an up-regulation of PI3K phosphorylation ratio and AKT phosphorylation ratio compared with those of the Control group(all P＜0.05).Cell experiments produced results similar to those of the animal experiment.After siRNA interference with SREBP1 expression,the expression levels of fibrosis marker proteins decreased(P＜0.05).Besides,the high expression of SREBP1 caused by TMAO was inhibited after HK2 cells were incubated with LY294002,a PI3K-AKT pathway inhibitor(P＜0.05).Conclusion TMAO may induce renal fibrosis by promoting the PI3K/AKT/SREBP1 pathway.关键词
氧化三甲胺/肾脏纤维化/PI3K/AKT通路/SREBP1Key words
Trimethylamine N-oxide/Renal fibrosis/PI3K/AKT pathway/SREBP1引用本文复制引用
陈静,黄英辉,赵景宏..氧化三甲胺通过PI3K/AKT/SREBP1通路诱导肾纤维化[J].四川大学学报（医学版）,2023,54(6):1105-1111,7.基金项目
国家自然科学基金(No.U22A20279、No.82322012、No.82170705)和重庆市英才计划(No.cstc2021jcyj-bgzxm0145)资助 （No.U22A20279、No.82322012、No.82170705）
