Ursolic acid attenuates diabetic mesangial cell injury through the up-regulation of autophagy via miRNA-21/PTEN/Akt/mTOR suppression

• Published in: PloS one Vol. 10; no. 2; p. e0117400
• Main Authors: Lu, Xinxing, Fan, Qiuling, Xu, Li, Li, Lin, Yue, Yuan, Xu, Yanyan, Su, Yan, Zhang, Dongcheng, Wang, Lining
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 17.02.2015; Public Library of Science (PLoS)
• Subjects: 1-Phosphatidylinositol 3-kinase; Acids; AKT protein; Animals; Autophagy; Autophagy - drug effects; Cell death; Cell growth; Cell injury; Cell Line; Cell number; Cell proliferation; Cell Proliferation - drug effects; Collagen; Collagen (type I); Collagen Type I - metabolism; Cytoprotection - drug effects; Diabetes; Diabetes mellitus; Diabetes Mellitus - pathology; Down-Regulation - drug effects; Electron microscopy; Extracellular matrix; Extracellular Matrix - drug effects; Extracellular Matrix - metabolism; Gene expression; Glucose; Glucose - pharmacology; Homology; Hospitals; Hypertrophy; Kidney - drug effects; Kinases; Mammals; Mesangial cells; Mesangial Cells - drug effects; Mesangial Cells - pathology; MicroRNA; MicroRNAs; MicroRNAs - metabolism; miRNA; Nephrology; Phagocytosis; Phagosomes; Phagosomes - drug effects; Phosphatidylinositol 3-Kinases - metabolism; Proteins; Proto-Oncogene Proteins c-akt - metabolism; PTEN Phosphohydrolase - metabolism; PTEN protein; Rapamycin; Rats; Rodents; Signal transduction; Signal Transduction - drug effects; Signaling; Tensin; TOR protein; TOR Serine-Threonine Kinases - metabolism; Triterpenes - pharmacology; Up-regulation; Up-Regulation - drug effects; Ursolic Acid; Western blotting; United States > US; China
• DOI: 10.1371/journal.pone.0117400
• ISSN: 1932-6203

To investigate the effect of ursolic acid on autophagy mediated through the miRNA-21-targeted phosphoinositide 3 kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway in rat mesangial cells cultured under high glucose (HG) conditions. Rat glomerular mesangial cells were cultured under normal glucose, HG, HG with the PI3K inhibitor LY294002 or HG with ursolic acid conditions. Cell proliferation and hypertrophy were assayed using an MTT assay and the ratio of total protein to cell number, respectively. The miRNA-21 expression was detected using RT-qPCR. The expression of phosphatase and tensin homolog (PTEN)/AKT/mTOR signaling signatures, autophagy-associated protein and collagen I was detected by western blotting and RT-qPCR. Autophagosomes were observed using electron microscopy. Compared with mesangial cells cultured under normal glucose conditions, the cells exposed to HG showed up-regulated miRNA-21 expression, down-regulated PTEN protein and mRNA expression, up-regulated p85PI3K, pAkt, pmTOR, p62/SQSTMI, and collagen I expression and down-regulated LC3II expression. Ursolic acid and LY294002 inhibited HG-induced mesangial cell hypertrophy and proliferation, down-regulated p85PI3K, pAkt, pmTOR, p62/SQSTMI, and collagen I expression and up-regulated LC3II expression. However, LY294002 did not affect the expression of miRNA-21 and PTEN. Ursolic acid down-regulated miRNA-21 expression and up-regulated PTEN protein and mRNA expression. Ursolic acid inhibits the glucose-induced up-regulation of mesangial cell miRNA-21 expression, up-regulates PTEN expression, inhibits the activation of PI3K/Akt/mTOR signaling pathway, and enhances autophagy to reduce the accumulation of the extracellular matrix and ameliorate cell hypertrophy and proliferation.