Department of Critical Care Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, P. R. China.
Department of Nephrology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, P.R China.
Bioengineered. 2022 Jan;13(1):774-788. doi: 10.1080/21655979.2021.2012919.
Mitochondrial injury-triggered podocyte apoptosis is a major risk factor for diabetic nephropathy (DN). However, the detailed relationship between mitochondrial homeostasis and podocyte apoptosis remains unclear. The present study aimed to explore the role and functional mechanism of germacrone in DN in type I diabetes (type I DN). A mouse model of type I DN was established by injecting streptozocin, and a podocyte injury model was constructed using high glucose (HG) induction. Histopathology was detected by hematoxylin and eosin and periodic acid-Schiff staining. Transmission electron microscopy and flow cytometry were used to evaluate the mitochondrial function. Germacrone simultaneously reduced blood glucose, 24 h proteinuria, and other nephrotic symptoms in a type 1 DN mouse model. Moreover, germacrone protected against mitochondrial damage, limited reactive oxygen species (ROS) accumulation, and restored glutathione peroxidase (GPX) activity and GPX4 protein expression, subsequently preventing podocyte apoptosis. Mechanistically, the increased miR-188-3p expression in type I DN mice was reversed in germacrone-challenged DN mice. HG induced miR-188-3p expression and the miR-188-3p antagonist abolished the HG-mediated increase in ROS. Notably, miR-188-3p was found to have a therapeutic effect against DN by aggravating mitochondrial damage and podocyte apoptosis. Germacrone alleviates DN progression in type I diabetes by limiting podocyte apoptosis, which was partly counteracted by miR-188-3p upregulation. The combination of germacrone and miR-188-3p antagonists is expected to be an effective therapeutic strategy for DN. diabetic nephropathy; Type I DN: DN in Type I diabetes; STZ: streptozocin; ROS: reactive oxygen species; NcRNAs: non-coding RNAs; UTR: untranslated regions; NC: negative control; BUN: blood urea nitrogen; BUA: blood uric acid; Ucr: urine creatinine; Scr: serum creatinine; PAS: Periodic Acid-Schiff; IF: Immunofluorescence; FISH: Fluorescence in situ hybridization; TUG1: taurine upregulated gene 1; GPX: Glutathione Peroxidase; GPX4: glutathione peroxidase 4; EMT: epithelial-mesenchymal transition.
线粒体损伤触发的足细胞凋亡是糖尿病肾病 (DN) 的主要危险因素。然而，线粒体动态平衡与足细胞凋亡之间的详细关系尚不清楚。本研究旨在探讨姜酮在 1 型糖尿病（1 型糖尿病肾病，type I DN）中的作用及其在 DN 中的功能机制。通过注射链脲佐菌素建立 1 型糖尿病肾病小鼠模型，通过高糖（HG）诱导建立足细胞损伤模型。通过苏木精和伊红以及过碘酸希夫染色检测组织病理学。通过透射电子显微镜和流式细胞术评估线粒体功能。姜酮同时降低 1 型糖尿病肾病小鼠模型的血糖、24 小时蛋白尿和其他肾病症状。此外，姜酮可防止线粒体损伤，限制活性氧（ROS）积累，并恢复谷胱甘肽过氧化物酶（GPX）活性和 GPX4 蛋白表达，从而防止足细胞凋亡。机制上，在姜酮处理的 DN 小鼠中，1 型糖尿病小鼠中 miR-188-3p 表达的增加得到了逆转。HG 诱导 miR-188-3p 表达，而 miR-188-3p 拮抗剂消除了 HG 介导的 ROS 增加。值得注意的是，miR-188-3p 通过加重线粒体损伤和足细胞凋亡对 DN 具有治疗作用。姜酮通过限制足细胞凋亡来减轻 1 型糖尿病中的 DN 进展，而 miR-188-3p 的上调部分抵消了这一作用。姜酮与 miR-188-3p 拮抗剂的联合有望成为 DN 的有效治疗策略。糖尿病肾病；1 型糖尿病肾病；DN 在 1 型糖尿病中；STZ：链脲佐菌素；ROS：活性氧；NcRNAs：非编码 RNA；UTR：非翻译区；NC：阴性对照；BUN：血尿素氮；BUA：血尿酸；Ucr：尿肌酐；Scr：血清肌酐；PAS：过碘酸希夫；IF：免疫荧光；FISH：荧光原位杂交；TUG1：牛磺酸上调基因 1；GPX：谷胱甘肽过氧化物酶；GPX4：谷胱甘肽过氧化物酶 4；EMT：上皮-间充质转化。
