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- Title
Renoprotective Effect of Isoorientin in Diabetic Nephropathy via Activating Autophagy and Inhibiting the PI3K-AKT-TSC2-mTOR Pathway.
- Authors
Kong, Zili; Xiao, Min; Wang, Bin; Zhang, Wenjie; Che, Kui; Lv, Wenshan; Wang, Yahao; Huang, Yajing; Zhao, Han; Zhao, Yanyun; Qi, Mengmeng; Chi, Jingwei; Wang, Yangang
- Abstract
Diabetic nephropathy (DN) is one of the most serious complications of diabetes and the most common cause of death. The autophagy of podocytes plays an important role in the pathogenesis of DN. Here, through screening the constituent compounds of practical and useful Chinese herbal formulas, we identified that isoorientin (ISO) strongly promoted the autophagy of podocytes and could effectively protect podocytes from high glucose (HG)-induced injury. ISO significantly improved autophagic clearance of damaged mitochondria under HG conditions. Through a proteomics-based approach, we identified that ISO could reverse the excessive phosphorylation of TSC2 S939 under HG conditions and stimulate autophagy through inhibition of the PI3K-AKT-TSC2-mTOR pathway. Furthermore, ISO was predicted to bind to the SH2 domain of PI3Kp85 β , which is crucial for the recruitment and activation of PI3K. The protective effect of ISO and its effects on autophagy and particularly on mitophagy were further proved using a DN mice model. To summarize, our study identified the protective effects of ISO against DN and demonstrated that ISO was a strong activator of autophagy, which could provide a basis for drug development.
- Subjects
BIOLOGICAL models; FLOW cytometry; IN vitro studies; STATISTICS; KIDNEYS; HERBAL medicine; IMMUNOGLOBULINS; CELL culture; AUTOPHAGY; PHOSPHOTRANSFERASES; ANIMAL experimentation; WESTERN immunoblotting; ONE-way analysis of variance; SIGNAL peptides; MTOR inhibitors; CHEMICAL reagents; QUANTITATIVE research; CELLULAR signal transduction; MITOCHONDRIA; PROTEOMICS; TRANSFERASES; FLAVONES; FLUORESCENT antibody technique; RESEARCH funding; DESCRIPTIVE statistics; MASS spectrometry; EPITHELIAL cells; MOLECULAR structure; GENETIC techniques; COMPUTER-assisted molecular modeling; GLUCOSE; DATA analysis software; DATA analysis; CHROMATOGRAPHIC analysis; DIABETIC nephropathies; CHINESE medicine; MICE; PHOSPHORYLATION; MEMBRANE potential; PHARMACODYNAMICS
- Publication
American Journal of Chinese Medicine, 2023, Vol 51, Issue 5, p1269
- ISSN
0192-415X
- Publication type
Article
- DOI
10.1142/S0192415X23500581