Fer-1 Alleviates Diabetic Nephropathy Injury by Inhibiting Ferroptosis Through HSF-1/HO-1 Pathway
10.3870/j.issn.1672-0741.25.04.011
- VernacularTitle:Fer-1通过HSF-1/HO-1通路抑制铁死亡减轻糖尿病肾病损伤
- Author:
Yu WANG
1
;
Hanyu WANG
;
Liu YANG
Author Information
1. 华中科技大学同济医学院附属协和医院内分泌科,武汉 430022
- Publication Type:Journal Article
- Keywords:
diabetic nephropathy;
cell death;
ferroptosis;
heat shock factor 1;
heme oxygenase-1
- From:
Acta Medicinae Universitatis Scientiae et Technologiae Huazhong
2025;54(3):305-311
- CountryChina
- Language:Chinese
-
Abstract:
Objective To elucidate the mechanistic role of ferrostatin-1(Fer-1)in the pathogenesis of diabetic nephropathy(DN).Methods Twenty spontaneous diabetic mice and ten negative control mice were used for in vivo experiments.The for-mer were randomly divided into a model group and a Fer-1 treatment group,with the treatment group receiving intraperitoneal injections of Fer-1(1 mg/kg).Levels of BUN,Scr,glucose,microalbuminuria,GSH,and iron were measured in the mice.Renal histopathological staining was performed to observe renal morphology.Western blot and immunohistochemistry were used to detect the expression of ferroptosis marker proteins,heat shock factor 1(HSF-1),and heme oxygenase-1(HO-1)in renal tis-sues.Human renal cortical proximal tubular epithelial cells(HK-2)were cultured and divided into three groups during in vitro experiments:control group,high glucose group(30 mmol/L),and Fer-1 treatment group(1μmol/L).Levels of GSH,MDA,4-HNE,and iron content were measured.Immunofluorescence experiment was used to assess the level of reactive oxygen species(ROS).Western blot was performed to detect the expressions of ferroptosis marker proteins,kidney injury molecule-1,neutro-phil gelatinase-associated lipocalin,HO-1,and HSF-1 in HK-2 cells.Results In the model group,renal pathological changes,in-cluding glomerular hypertrophy,mesangial matrix expansion,glycogen accumulation,and fibrosis,were observed.Compared with the control group,levels of BUN,Scr,glucose,and urinary microalbumin were increased,GSH content was decreased,and iron level was elevated in the model group(all P＜0.05).The expression of HSF-1 protein in the kidneys of the model group was lower than that in the control group,while HO-1 protein expression was higher.The Fer-1 treatment group exhibited the oppo-site trend.(both P＜0.05).GSH expression was decreased,and iron content,MDA,and 4-HNE levels were increased in the high glucose group(all P＜0.05).Immunofluorescence result revealed that,compared with the control group,ROS level was higher in the high glucose group(all P＜0.05).Additionally,the high glucose group showed increased expressions of KIM-1,NGAL,and HO-1,along with reduced HSF-1 expression,whereas the Fer-1 treatment group exhibited the opposite trend.(all P＜0.05).Conclusion Both in vivo and in vitro experiments have demonstrated that ferroptosis plays a significant role in the de-velopment and progression of DN.Fer-1 may alleviate DN injury by upregulating ferroptosis through the HSF-1/HO-1 signaling pathway.
