title: Ursolic acid attenuates diabetic mesangial cell injury through the up-regulation of autophagy via miRNA-21/PTEN/Akt/mTOR suppression.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Nephrology, the First Hospital of China Medical University, Shenyang, 110001, China; Department of nephrology, the People's Hospital of Liaoning Province, Shenyang, 110001, China.
authors.forename: Xinxing
authors.initials: X
authors.lastname: Lu
authors.affiliation: Department of Nephrology, the First Hospital of China Medical University, Shenyang, 110001, China.
authors.forename: Qiuling
authors.initials: Q
authors.lastname: Fan
authors.affiliation: Department of Nephrology, the First Hospital of China Medical University, Shenyang, 110001, China.
authors.forename: Li
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Nephrology, the First Hospital of China Medical University, Shenyang, 110001, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Nephrology, the First Hospital of China Medical University, Shenyang, 110001, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yue
authors.affiliation: Department of Nephrology, the First Hospital of China Medical University, Shenyang, 110001, China.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of nephrology, the People's Hospital of Liaoning Province, Shenyang, 110001, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Su
authors.affiliation: Department of nephrology, the People's Hospital of Liaoning Province, Shenyang, 110001, China.
authors.forename: Dongcheng
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Department of Nephrology, the First Hospital of China Medical University, Shenyang, 110001, China.
authors.forename: Lining
authors.initials: L
authors.lastname: Wang
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D024042:Collagen Type I / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects; D003920:Diabetes Mellitus / Q000473:pathology*; D015536:Down-Regulation / Q000187:drug effects; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology; D006984:Hypertrophy; D007668:Kidney / Q000187:drug effects; D050527:Mesangial Cells / Q000187:drug effects / Q000473:pathology*; D035683:MicroRNAs / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D010588:Phagosomes / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014315:Triterpenes / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects*; D000097245:Ursolic Acid
chemical_list: D024042:Collagen Type I; D005947:Glucose; D035683:MicroRNAs; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D014315:Triterpenes; D000097245:Ursolic Acid; C546082:mirn21 microRNA, rat