Zhu Yuexin, Dong Changqing, Xu Zhiheng, Lou Yan, Tian Na, Guan Yucan, Nie Ping, Luo Manyu, Luo Ping
Department of Nephrology, The Second Hospital of Jilin University, Changchun, P.R. China.
Department of Radiology, Changchun Stomatological Hospital, Changchun, P.R. China.
Antioxid Redox Signal. 2025 Jun;42(16-18):807-826. doi: 10.1089/ars.2024.0575. Epub 2024 Nov 26.
Diabetic nephropathy (DN) is a major cause of end-stage renal disease, with no therapeutic interventions available to control its progression. Ferroptosis, an iron-dependent regulated cell death characterized by lipid peroxidation, plays a pivotal role in the pathogenesis of DN. Human umbilical cord mesenchymal stem cells (hUCMSCs) are an effective treatment modality for DN; however, the underlying mechanism of action remains unclear. The aim of the present study was to investigate whether hUCMSCs alleviate DN via inhibiting ferroptosis and its molecular mechanisms in type 2 diabetic mice and high-glucose and palmitate-stimulated human renal tubular epithelial cell (HK-11) models. Our findings revealed that hUCMSCs improved the renal structure and function and tubular injuries. HUCMSC treatment can inhibit ferroptosis by decreasing iron content, reducing reactive oxygen species, malondialdehyde and 4-hydroxynonenal generation, decreasing the expression of positive ferroptosis mediator transferrin receptor 1 and long-chain acyl-CoA synthetase 4, and enhancing the expression of negative ferroptosis mediators ( ferritin heavy chain, glutathione peroxidase 4, and system Xc-cystine/glutamate reverse transporter). Mechanistically, hUCMSC treatment inhibited c-Jun N-terminal kinase (JNK) and Kelch-like ECH-associated protein 1 (KEAP1) activation while increasing the expression of nuclear factor erythroid 2-related factor 2 (NRF2). Furthermore, pretreatment of HK-11 cells with NRF2 siRNA, the JNK inhibitor SP600125, or the JNK agonist anisomycin demonstrated the regulation of the JNK/KEAP1/NRF2 signaling pathway by hUCMSCs. HUCMSCs inhibit ferroptosis in DN via the JNK/KEAP1/NRF2 signaling pathway, providing a new perspective and scientific evidence for treating DN. 42, 807-826.
糖尿病肾病（DN）是终末期肾病的主要原因，目前尚无控制其进展的治疗干预措施。铁死亡是一种以脂质过氧化为特征的铁依赖性调节性细胞死亡，在DN的发病机制中起关键作用。人脐带间充质干细胞（hUCMSCs）是治疗DN的一种有效方法；然而，其潜在的作用机制仍不清楚。本研究的目的是在2型糖尿病小鼠以及高糖和棕榈酸刺激的人肾小管上皮细胞（HK-11）模型中，研究hUCMSCs是否通过抑制铁死亡及其分子机制来减轻DN。我们的研究结果表明，hUCMSCs改善了肾脏结构和功能以及肾小管损伤。hUCMSC治疗可通过降低铁含量、减少活性氧、丙二醛和4-羟基壬烯醛的生成、降低铁死亡正向调节因子转铁蛋白受体1和长链酰基辅酶A合成酶4的表达以及增强铁死亡负向调节因子（铁蛋白重链、谷胱甘肽过氧化物酶4和系统Xc-胱氨酸/谷氨酸逆向转运体）的表达来抑制铁死亡。机制上，hUCMSC治疗抑制了c-Jun氨基末端激酶（JNK）和 Kelch样ECH相关蛋白1（KEAP1）的激活，同时增加了核因子红细胞2相关因子2（NRF2）的表达。此外，用NRF2小干扰RNA、JNK抑制剂SP600125或JNK激动剂茴香霉素对HK-11细胞进行预处理，证明了hUCMSCs对JNK/KEAP1/NRF2信号通路的调节作用。hUCMSCs通过JNK/KEAP1/NRF2信号通路抑制DN中的铁死亡，为治疗DN提供了新的视角和科学依据。42, 807 - 826。
