Tanshinone IIA suppresses ferroptosis to attenuate renal podocyte injury in diabetic nephropathy through the embryonic lethal abnormal visual-like protein 1 and acyl-coenzyme A synthetase long-chain family member 4 signaling pathway

IF 3.1 3区医学 Q2 ENDOCRINOLOGY & METABOLISM

Journal of Diabetes Investigation Pub Date : 2024-04-22 DOI:10.1111/jdi.14206

Shuai Zhu, Zhiqiang Kang, Fengjiao Zhang

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Abstract

Aims/Introduction

Tanshinone IIA (TIIA) is one of the main components of the root of the red-rooted Salvia miltiorrhiza Bunge. However, the molecular mechanisms underlying TIIA-mediated protective effects in diabetic nephropathy (DN) are still unclear.

Materials and Methods

High glucose (HG)-induced mouse podocyte cell line (MPC5) cells were used as the in vitro model of DN and treated with TIIA. Cell viability, proliferation and apoptosis were detected using 3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide, 5-ethynyl-2′-deoxyuridine and flow cytometry assays. The protein levels were assessed using western blot assay. The levels of inflammatory factors were deleted by enzyme-linked immunoassay. Fe⁺ level, reactive oxygen species, malondialdehyde and glutathione products were detected using special assay kits. After ENCORI prediction, the interaction between embryonic lethal abnormal visual-like protein 1 (ELAVL1) and acyl-coenzyme A synthetase long-chain family member 4 (ACSL4) was verified using co-immunoprecipitation assay and dual-luciferase reporter assays. ACSL4 messenger ribonucleic acid expression was measured using real-time quantitative polymerase chain reaction.

Results

TIIA repressed HG-induced MPC5 cell apoptosis, inflammatory response and ferroptosis. ACSL4 upregulation relieved the repression of TIIA on HG-mediated MPC5 cell injury and ferroptosis. ELAVL1 is bound with ACSL4 to positively regulate the stability of ACSL4 messenger ribonucleic acid. TIIA hindered HG-triggered MPC5 cell injury and ferroptosis by regulating the ELAVL1–ACSL4 pathway. TIIA blocked DN progression in in vivo research.

Conclusion

TIIA treatment restrained HG-caused MPC5 cell injury and ferroptosis partly through targeting the ELAVL1–ACSL4 axis, providing a promising therapeutic target for DN treatment.

Abstract Image

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丹参酮 IIA 可通过胚胎致死性异常视觉样蛋白 1 和酰基辅酶 A 合成酶长链家族成员 4 信号通路抑制糖尿病肾病中的铁蛋白沉积，从而减轻肾荚膜细胞损伤。

目的/简介丹参酮 IIA（TIIA）是红根丹参（Salvia miltiorrhiza Bunge）根部的主要成分之一。材料与方法用高糖（HG）诱导的小鼠荚膜细胞系（MPC5）细胞作为糖尿病肾病（DN）的体外模型，并用 TIIA 处理。使用 3-（4，5-二甲基噻唑基-2）-2，5-二苯基溴化四氮唑、5-乙炔基-2'-脱氧尿苷和流式细胞术检测细胞活力、增殖和凋亡。蛋白质水平则采用 Western 印迹法进行评估。炎症因子水平通过酶联免疫测定法进行检测。使用专用检测试剂盒检测铁+水平、活性氧、丙二醛和谷胱甘肽产物。经过 ENCORI 预测，利用共免疫沉淀法和双荧光素酶报告实验验证了胚胎致死性异常视觉样蛋白 1（ELAVL1）与酰辅酶 A 合成酶长链家族成员 4（ACSL4）之间的相互作用。结果STIIA抑制了HG诱导的MPC5细胞凋亡、炎症反应和铁变态反应。ACSL4的上调缓解了TIIA对HG介导的MPC5细胞损伤和铁凋亡的抑制作用。ELAVL1与ACSL4结合，正向调节ACSL4信使核糖核酸的稳定性。TIIA通过调节ELAVL1-ACSL4通路，阻碍了HG触发的MPC5细胞损伤和铁突变。结论TIIA治疗可部分通过靶向ELAVL1-ACSL4轴抑制HG引发的MPC5细胞损伤和铁突变，为DN治疗提供了一个有前景的治疗靶点。

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来源期刊

Journal of Diabetes Investigation ENDOCRINOLOGY & METABOLISM-

CiteScore

6.50

自引率

9.40%

发文量

218

审稿时长

6-12 weeks

期刊介绍： Journal of Diabetes Investigation is your core diabetes journal from Asia; the official journal of the Asian Association for the Study of Diabetes (AASD). The journal publishes original research, country reports, commentaries, reviews, mini-reviews, case reports, letters, as well as editorials and news. Embracing clinical and experimental research in diabetes and related areas, the Journal of Diabetes Investigation includes aspects of prevention, treatment, as well as molecular aspects and pathophysiology. Translational research focused on the exchange of ideas between clinicians and researchers is also welcome. Journal of Diabetes Investigation is indexed by Science Citation Index Expanded (SCIE).