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目的 探讨BTB域和CNC同系物1（BACH1）在糖尿病肾病（DN）发生发展中的作用及其通过核因子E2相关因子2/血红素加氧酶-1（Nrf2/HO-1）信号通路影响铁死亡的分子机制。方法 8周龄db/db小鼠随机分为模型组、BACH1-shRNA敲低组及阴性对照组，并以db/m小鼠作为正常对照。通过肾脏原位注射慢病毒敲低肾组织BACH1表达，检测小鼠肾功能指标血肌酐（Scr）、尿素氮（BUN）、尿微量白蛋白/肌酐比值（UACR）；通过苏木精-伊红（HE）、过碘酸-雪夫（PAS）和Masson染色观察肾脏病理变化；试剂盒检测氧化应激指标超氧化物歧化酶（SOD）、丙二醛（MDA）、还原型谷胱甘肽/氧化型谷胱甘肽（GSH/GSSG）、活性氧（ROS）及铁死亡相关指标亚铁离子含量、脂质过氧化物（LPO）；利用Westernblot法和实时荧光定量PCR技术检测BACH1、核Nrf2、HO-1、谷胱甘肽过氧化物酶4（GPX4）、溶质载体家族7成员11（SLC7A11）的表达。结果 与db/m组相比，db/db组小鼠肾组织中BACH1的mRNA和蛋白表达均显著上调，并伴随Scr、BUN和UACR显著升高，肾脏出现明显的病理学改变；同时SOD活性显著降低，MDA含量显著升高，GSH/GSSG比值显著下降，ROS水平显著升高；组织亚铁离子含量和LPO水平显著升高，GPX4和SLC7A11表达显著下调，Nrf2核转位水平下降。而敲低BACH1后，db/db小鼠Scr、BUN和UACR均显著降低，肾脏病理损伤明显减轻；同时SOD活性升高，MDA含量降低，GSH/GSSG比值回升，ROS水平降低；铁死亡进程受到抑制，组织铁含量和LPO水平显著降低，GPX4和SLC7A11表达显著上调。同时，敲低BACH1显著促进了Nrf2核转位，并上调了其下游靶蛋白HO-1的表达。结论BACH1在DN中高表达，其可能通过抑制Nrf2/HO-1通路，加剧氧化应激与铁死亡，从而促进DN的进展。敲低BACH1可激活Nrf2/HO-1通路，发挥肾脏保护作用，为DN治疗提供了新的靶点。
Abstract：Objective To investigate the role of BTB domain and CNC homolog 1 (BACH1) in the development of diabetic nephropathy (DN) and its molecular mechanism by which it mediates ferroptosis through the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) signaling pathway. Methods Eight-week-old db/db mice were randomly divided into model， BACH1-shRNA knockdown， and negative control groups， with db/m mice serving as normal controls. BACH1 expression in renal tissue was knocked down by intraparenchymal injection of lentivirus. Renal function parameters， including serum creatinine (Scr)， blood urea nitrogen (BUN)， and urine albumin-to-creatinine ratio (UACR)， were measured. Renal pathological changes were observed via hematoxylin-eosin (HE)， periodic acid-Schiff (PAS)， and Masson staining. Oxidative stress indicators， including superoxide dismutase (SOD)， malondialdehyde (MDA)， reduced glutathione/oxidized glutathione (GSH/GSSG)， and reactive oxygen species (ROS)， as well as ferroptosis-related indicators， including ferrous ion content and lipid peroxide (LPO)， were detected using commercial kits. The expression levels of BACH1， nuclear Nrf2， HO-1， glutathione peroxidase 4 (GPX4)， and solute carrier family 7 member 11 (SLC7A11) were detected by Western blot and real-time quantitative fluorescent PCR. Results Compared with the db/m group， the db/db group showed upregulated BACH1 mRNA and protein expression in renal tissues. This was accompanied by significant increases in Scr， BUN， and UACR， along with marked renal pathological changes. In addition， SOD activity was significantly decreased， MDA content was increased， the GSH/GSSG ratio was reduced， and ROS levels were elevated. Tissue iron content and LPO levels were significantly increased， while GPX4 and SLC7A11 expression were downregulated， and Nrf2 nuclear translocation was reduced. After BACH1 knockdown， Scr， BUN， and UACR were significantly reduced， and renal pathological injury was markedly alleviated. SOD activity increased， MDA content decreased， GSH/GSSG ratio recovered， and ROS levels decreased. Ferroptosis was inhibited， as evidenced by significantly reduced tissue iron content and LPO levels， along with significantly upregulated GPX4 and SLC7A11 expression. Furthermore， BACH1 knockdown significantly promoted Nrf2 nuclear translocation and upregulated the expression of its downstream target protein HO-1. Conclusion BACH1 is highly expressed in DN and may promote the progression of DN by inhibiting the Nrf2/HO-1 pathway， thereby exacerbating oxidative stress and ferroptosis. Knockdown of BACH1 activates the Nrf2/HO-1 pathway， exerting a renal protective effect， and provides a new potential therapeutic target for DN.
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基本信息:
DOI：10.13423/j.cnki.cjcmi.010183
中图分类号:R587.2;R692.9
引用信息:
[1]龙圣海,王脉桃,唐齐林,等.BACH1调控Nrf2/HO-1轴在糖尿病肾病铁死亡和氧化应激的作用[J].细胞与分子免疫学杂志().DOI:10.13423/j.cnki.cjcmi.010183.
基金信息:
湖南省自然科学基金项目（2025JJ81088）
2026-07-23
2026-07-23
2026-07-23