title: Fluvastatin prevents oxidized low-density lipoprotein-induced injury of renal tubular epithelial cells by inhibiting the phosphatidylinositol 3-kinase/Akt-signaling pathway.
abstract: BACKGROUND
  Lipid abnormalities may play a role in the progression of nephrosis. Recent studies have demonstrated that oxidized low-density lipoprotein (oxLDL) appears to be a detrimental factor for the glomerular mesangium and podocytes. The aim of the present study is to identify the potential effects of oxLDL on tubular epithelial cells (TECs) in vitro and to investigate its associated signal transduction pathway, as well as to examine whether fluvastatin reverses the responses of TECs to oxLDL.
  
  
  METHODS
  Hypertrophy of cells was evaluated by measurements of [ 3 H]-leucine incorporation, the total protein contents of cells and cell cycle determined by fluorescence-activated cell sorter (FACS) flow cytometry. TGF-beta beta 1 was quantified by enzyme-linked immunosorbent assay (ELISA). An Akt kinase assay kit was used to determine Akt activity. Akt phosphorylation was determined by Western blot. Wortmannin, the specific inhibitor of phosphatidylinositol-3-kinase (PI3K), was used to reflect the possible involvement of PI3K.
  
  
  RESULTS
  The results show that exposure to oxLDL increased Akt activity and phosphorylation in a dose-dependent manner. Stimulating with oxLDL increases the incorporation of [ 3 H]-leucine by 1.3 fold and causes a 1.6-fold increase in total protein content. Compared with that for the control group, the percentage of cells in the G0-G1 phase is 19% higher in the oxLDL group. And the secretion of TGF-beta beta 1 is increased when incubated with oxLDL. Wortmannin treatment significantly inhibits the effects induced by oxLDL, indicating that the effect of oxLDL is PI3K dependent. Fluvastatin significantly decreases Akt phosphorylation and activity in a dose-dependent manner. Incorporation of [ 3 H]-leucine, total protein content, cell cycle distribution and TGF-beta beta 1 expression are all attenuated by fluvastatin, and these effects are prevented with mevalonate.
  
  
  CONCLUSIONS
  These results demonstrate that the PI3K/Akt-signaling transduction system is activated by oxLDL, and may mediate the cell hypertrophy and up-regulation of TGF-beta beta 1 expression from TECs. Fluvastatin may inhibit the activity of PI3K/Akt and prevent injury to TECs from oxLDL.
authors.affiliation: Department of Nephrology, Renmin Hospital, Wuhan University, Wuhan, China. guilichu@yahoo.com.cn
authors.forename: Guili
authors.initials: G
authors.lastname: Chu
authors.forename: Ruhan
authors.initials: R
authors.lastname: Jia
authors.forename: Dingping
authors.initials: D
authors.lastname: Yang
mesh_terms: D000818:Animals; D018929:Cell Culture Techniques; D002460:Cell Line; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D000077340:Fluvastatin; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008077:Lipoproteins, LDL; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; D000077340:Fluvastatin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt