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 journalArticlepeer-review

50 Citations (Scopus)

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

Keywords

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

ASJC Scopus subject areas

  • Pharmacology

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