Inhibiting glycogen synthase kinase-3 reduces endotoxaemic acute renal failure by down-regulating inflammation and renal cell apoptosis

Br J Pharmacol. 2009 Jul;157(6):1004-13. doi: 10.1111/j.1476-5381.2009.00284.x. Epub 2009 Jun 5.


Background and purpose: 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.

Experimental approach: 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.

Key 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 and implications: These results suggest that GSK-3 inhibition protects against endotoxaemic acute renal failure mainly by down-regulating pro-inflammatory TNF-alpha and RANTES.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Kidney Injury / drug therapy
  • Acute Kidney Injury / enzymology*
  • Acute Kidney Injury / pathology*
  • Animals
  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Apoptosis Regulatory Proteins / antagonists & inhibitors*
  • Apoptosis Regulatory Proteins / physiology
  • Cells, Cultured
  • Down-Regulation / drug effects
  • Down-Regulation / physiology*
  • Endotoxins / antagonists & inhibitors
  • Endotoxins / toxicity
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors*
  • Glycogen Synthase Kinase 3 / physiology
  • Inflammation Mediators / antagonists & inhibitors*
  • Inflammation Mediators / physiology
  • Lipopolysaccharides / antagonists & inhibitors
  • Lipopolysaccharides / toxicity
  • Male
  • Mice
  • Mice, Inbred C3H
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use*
  • Rats
  • Thiadiazoles / pharmacology
  • Thiadiazoles / therapeutic use


  • 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione
  • Apoptosis Regulatory Proteins
  • Endotoxins
  • Inflammation Mediators
  • Lipopolysaccharides
  • Protein Kinase Inhibitors
  • Thiadiazoles
  • endotoxin, Escherichia coli
  • Glycogen Synthase Kinase 3