RETRACTED ARTICLE: miR-188-3p abolishes germacrone-mediated podocyte protection in a mouse model of diabetic nephropathy in type I diabetes through triggering mitochondrial injury

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Abstract
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. Abbreviations 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
Funding Information
  • Zhejiang Provincial Traditional Chinese Medicine Science and Technology Project (Grant Number: 2022ZB273 and 2021ZB219)
  • Cultivation Program for Excellent Young Talents
  • Construction of Key Projects by Zhejiang Provincial Ministry (Grant Number: WKJ-ZJ-2017)
  • Zhejiang Province Chinese Medicine Modernization Program (Grant Number: 2020ZX001)
  • Zhejiang Provincial Natural Science Foundation of China (LY21H010001)
  • Key Project of Scientific Research Foundation of Chinese Medicine (Grant Number: 2022ZZ002)

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