Augmenter of liver regeneration knockout aggravates tubular ferroptosis and macrophage activation by regulating carnitine palmitoyltransferase-1A-induced lipid metabolism in diabetic nephropathy

作者全名：Zhang, Yuanyuan; Zhang, Zheng; Huang, Lili; Wang, Chunxia; Yang, Pengfei; Zhang, Ling; Liao, Xiaohui

作者地址：[Zhang, Yuanyuan; Zhang, Zheng; Huang, Lili; Wang, Chunxia; Yang, Pengfei; Zhang, Ling; Liao, Xiaohui] Chongqing Med Univ, Affiliated Hosp 2, Dept Nephrol, Chongqing, Peoples R China; [Zhang, Yuanyuan] Chongqing Red Cross Hosp, Peoples Hosp Jiangbei Dist, Dept Nephrol, Chongqing, Peoples R China; [Zhang, Zheng] Chongqing Med Univ, Dept Cell Biol & Genet, Chongqing, Peoples R China; [Liao, Xiaohui] Chongqing Med Univ, Ctr Lipid Res, Kuanren Lab Translat Lipidol, Affiliated Hosp 2, Chongqing, Peoples R China

通信作者：Zhang, L; Liao, XH (通讯作者)，Chongqing Med Univ, Affiliated Hosp 2, Dept Nephrol, Chongqing, Peoples R China.

来源：ACTA PHYSIOLOGICA

ESI学科分类：BIOLOGY & BIOCHEMISTRY

WOS号：WOS:001227227600001

JCR分区：Q1

影响因子：5.6

年份：2024

卷号：240

期号：7

开始页：　

结束页：　

文献类型：Article

关键词：augmenter of liver regeneration; carnitine palmitoyltransferase-1A; diabetic nephropathy; ferroptosis; lipid droplet-mitochondrial coupling; macrophage activation; mitochondria

摘要：AimFerroptosis is a novel type of programmed cell death that performs a critical function in diabetic nephropathy (DN). Augmenter of liver regeneration (ALR) exists in the inner membrane of mitochondria, and inhibits inflammation, apoptosis, and oxidative stress in acute kidney injury; however, its role in DN remains unexplored. Here, we aimed to identify the role of ALR in ferroptosis induction and macrophage activation in DN.MethodsThe expression of ALR was examined in DN patients, db/db DN mice, and HK-2 cells treated with high glucose (HG). The effects of ALR on ferroptosis and macrophage activation were investigated with ALR conditional knockout, lentivirus transfection, transmission electron microscopy, qRT-PCR and western blotting assay. Mass spectrometry and rescue experiments were conducted to determine the mechanism of ALR.ResultsALR expression was reduced in the kidney tissues of DN patients and mice, serum of DN patients, and HG-HK-2 cells. Moreover, the inhibition of ALR promoted ferroptosis, macrophage activation, and DN progression. Mechanistically, ALR can directly bind to carnitine palmitoyltransferase-1A (CPT1A), the key rate-limiting enzyme of fatty acid oxidation (FAO), and inhibit the expression of CPT1A to regulate lipid metabolism involving FAO and lipid droplet-mitochondrial coupling in DN.ConclusionTaken together, our findings revealed a crucial protective role of ALR in ferroptosis induction and macrophage activation in DN and identified it as an alternative diagnostic marker and therapeutic target for DN.

基金机构：Medical Scientific Research Project of the Jiangbei District Health Commission

基金资助正文：No Statement Availabler No Statement Availabler No Statement Availabler No Statement Availabler No Statement Available