title: Inhibiting glycogen synthase kinase-3 reduces endotoxaemic acute renal failure by down-regulating inflammation and renal cell apoptosis.
abstract: OBJECTIVE
  Excessive inflammation and apoptosis are pathological features of endotoxaemic acute renal failure. Activation of glycogen synthase kinase-3 (GSK-3) is involved in inflammation and apoptosis. We investigated the effects of inhibiting GSK-3 on lipopolysaccharide (LPS)-induced acute renal failure, nuclear factor-kappaB (NF-kappaB), inflammation and apoptosis.
  
  
  METHODS
  The effects of inhibiting GSK-3 with inhibitors, including lithium chloride (LiCl) and 6-bromo-indirubin-3'-oxime (BIO), on LPS-treated (15 mg x kg(-1)) C3H/HeN mice (LiCl, 40 mg x kg(-1) and BIO, 2 mg x kg(-1)) and LPS-treated (1 microg x mL(-1)) renal epithelial cells (LiCl, 20 mM and BIO, 5 microM) were studied. Mouse survival was monitored and renal function was analysed by histological and serological examination. Cytokine and chemokine production, and cell apoptosis were measured by enzyme-linked immunosorbent assay and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labelling staining, respectively. Activation of NF-kappaB and GSK-3 was determined by immunostaining and Western blotting, respectively.
  
  
  RESULTS
  Mice treated with GSK-3 inhibitors showed decreased mortality, renal tubular dilatation, vacuolization and sloughing, blood urea nitrogen, creatinine and renal cell apoptosis in response to endotoxaemia. Inhibiting GSK-3 reduced LPS-induced tumour necrosis factor-alpha (TNF-alpha) and CCL5/RANTES (released upon activation of normal T-cells) in vivo in mice and in vitro in murine kidney cortical collecting duct epithelial M1 cells. Inhibiting GSK-3 did not block TNF-alpha-induced cytotoxicity in rat kidney proximal tubular epithelial NRK52E or in M1 cells.
  
  
  CONCLUSIONS
  These results suggest that GSK-3 inhibition protects against endotoxaemic acute renal failure mainly by down-regulating pro-inflammatory TNF-alpha and RANTES.
authors.affiliation: Department of Microbiology and Immunology, National Cheng Kung University Medical College, Tainan 701, Taiwan.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.forename: W C
authors.initials: WC
authors.lastname: Huang
authors.forename: C Y
authors.initials: CY
authors.lastname: Wang
authors.forename: C C
authors.initials: CC
authors.lastname: Tsai
authors.forename: C L
authors.initials: CL
authors.lastname: Chen
authors.forename: Y T
authors.initials: YT
authors.lastname: Chang
authors.forename: J I
authors.initials: JI
authors.lastname: Kai
authors.forename: C F
authors.initials: CF
authors.lastname: Lin
mesh_terms: D058186:Acute Kidney Injury / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology*; D004731:Endotoxins / Q000037:antagonists & inhibitors / Q000633:toxicity; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000502:physiology; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors* / Q000502:physiology; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000633:toxicity; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D013830:Thiadiazoles / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: C494356:4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione; D051017:Apoptosis Regulatory Proteins; D004731:Endotoxins; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D047428:Protein Kinase Inhibitors; D013830:Thiadiazoles; C044101:endotoxin, Escherichia coli; D038362:Glycogen Synthase Kinase 3