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

Yi Wang, Wei-Ching Huang, Chi-Yun Wang, Cheng-Chieh Tsai, Chia-Ling Chen, Yu-Tzu Chang, Jui-In Kai, C. F. Lin

Research output: Contribution to journalArticle

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Abstract

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-kB (NF-kΒ), inflammation and apoptosis. Experimental approach: The effects of inhibiting GSK-3 with inhibitors, including lithium chloride (LiCl) and 6-bromoindirubin-3-oxime (BIO), on LPS-treated (15 mg-kg-1) C3H/HeN mice (LiCl, 40 mg-kg-1 and BIO, 2 mg-kg-1) and LPS-treated (1 mg-mL-1) renal epithelial cells (LiCl, 20 mM and BIO, 5 mM) 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-kB 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-a (TNF-a) 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-a-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-a and RANTES.

Original languageEnglish
Pages (from-to)1004-1013
Number of pages10
JournalBritish Journal of Pharmacology
Volume157
Issue number6
DOIs
Publication statusPublished - 2009

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Glycogen Synthase Kinase 3
Acute Kidney Injury
Apoptosis
Inflammation
Kidney
Lithium Chloride
Lipopolysaccharides
Chemokine CCL5
Oximes
Tumor Necrosis Factor-alpha
Collecting Kidney Tubules
Epithelial Cells
Endotoxemia
DNA Nucleotidylexotransferase
Inbred C3H Mouse
NF-kappa B
Blood Urea Nitrogen
Biotin
Chemokines
Dilatation

Keywords

  • Acute renal failure
  • Apoptosis
  • GSK-3
  • Inflammation
  • Lipopolysaccharide
  • TNF-α

ASJC Scopus subject areas

  • Pharmacology

Cite this

Inhibiting glycogen synthase kinase-3 reduces endotoxaemic acute renal failure by down-regulating inflammation and renal cell apoptosis. / Wang, Yi; Huang, Wei-Ching; Wang, Chi-Yun; Tsai, Cheng-Chieh; Chen, Chia-Ling; Chang, Yu-Tzu; Kai, Jui-In; Lin, C. F.

In: British Journal of Pharmacology, Vol. 157, No. 6, 2009, p. 1004-1013.

Research output: Contribution to journalArticle

Wang, Yi ; Huang, Wei-Ching ; Wang, Chi-Yun ; Tsai, Cheng-Chieh ; Chen, Chia-Ling ; Chang, Yu-Tzu ; Kai, Jui-In ; Lin, C. F. / Inhibiting glycogen synthase kinase-3 reduces endotoxaemic acute renal failure by down-regulating inflammation and renal cell apoptosis. In: British Journal of Pharmacology. 2009 ; Vol. 157, No. 6. pp. 1004-1013.
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AU - Tsai, Cheng-Chieh

AU - Chen, Chia-Ling

AU - Chang, Yu-Tzu

AU - Kai, Jui-In

AU - Lin, C. F.

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AB - 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-kB (NF-kΒ), inflammation and apoptosis. Experimental approach: The effects of inhibiting GSK-3 with inhibitors, including lithium chloride (LiCl) and 6-bromoindirubin-3-oxime (BIO), on LPS-treated (15 mg-kg-1) C3H/HeN mice (LiCl, 40 mg-kg-1 and BIO, 2 mg-kg-1) and LPS-treated (1 mg-mL-1) renal epithelial cells (LiCl, 20 mM and BIO, 5 mM) 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-kB 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-a (TNF-a) 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-a-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-a and RANTES.

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