Thalidomide alleviates ferroptosis and oxidative stress in diabetic nephropathy by upregulating nuclear factor E2-related factor 2/heme oxygenase 1/glutathione peroxidase 4 signaling pathway
10.3760/cma.j.cn441217-20240918-00929
- VernacularTitle:沙利度胺通过上调核因子E2相关因子2/血红素加氧酶1/谷胱甘肽过氧化物酶4信号通路减轻糖尿病肾病铁死亡和氧化应激
- Author:
Lu ZHAI
1
;
Xiaoxiao XUE
;
Xiaomei LIU
;
Yuxiao MA
;
Hongxia ZHANG
Author Information
1. 山西医科大学附属山西省人民医院内分泌科，太原 030012
- Publication Type:Journal Article
- Keywords:
Diabetic nephropathies;
Ferroptosis;
Thalidomide;
Nuclear factor E2-related factor 2;
Heme oxygenase 1;
Glutathione peroxidase 4
- From:
Chinese Journal of Nephrology
2025;41(4):276-281
- CountryChina
- Language:Chinese
-
Abstract:
To investigate the potential protective effect of thalidomide (THD) on diabetic nephropathy (DN) and its underlying mechanisms. Twenty-four C57BL/6J mice were randomly divided into control, DN and DN+THD200 groups by random number table method. The DN mouse model was established via intraperitoneal injection of streptozotocin. The DN+THD200 group received THD treatment (200 mg·kg -1·d -1) for 8 weeks. Blood and urine biochemical parameters, as well as renal histopathological changes, were compared among the three groups. For in vitro experiments, a high glucose (HG)-induced injury model was established in mouse glomerular podocytes (MPC5). Cells were divided into control (NG), HG, HG+DMSO, HG+THD100 (100 μg/ml), and HG+THD200 (200 μg/ml) groups. THD-treated cells were exposed to THD for 24 h. Western blotting and real-time quantitative PCR were performed to respectively detect protein and mRNA expression levels of ferroptosis-related molecules, including nuclear factor erythroid 2-related factor 2 (NRF2), heme oxygenase 1 (HO-1), and glutathione peroxidase 4 (GPX4). Immunofluorescence was used to evaluate the expression of solute carrier family 7 member 11 (SLC7A11) and 4-hydroxynonenal (4-HNE). The results showed that, compared with control group, DN group exhibited significantly lower blood urea nitrogen, serum creatinine and 24 h urinary albumin levels (all P<0.05). Compared with DN group, DN+THD200 group exhibited significantly lower blood urea nitrogen, serum creatinine and 24 h urinary albumin levels (all P<0.05). Histopathological examination revealed glomerular expansion, mesangial widening, and basement membrane thickening in DN group compared to control group, which were markedly ameliorated by THD treatment. In vitro, HG group showed significantly decreased protein and mRNA expression levels of GPX4, NRF2 and HO-1 compared to NG group. Both HG+THD100 and HG+THD200 groups exhibited upregulated expression levels of these proteins and corresponding mRNA compared to HG group (all P<0.05). Immunofluorescence demonstrated HG group had enhanced 4-HNE fluorescence intensity and reduced SLC7A11 fluorescence intensity, which were reversed by THD treatment. THD alleviates renal injury in DN mice and mitigates HG-induced ferroptosis in MPC5 cells, potentially via activation of NRF2-HO-1-GPX4 signaling pathway.
