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

Y. Wang, W. C. Huang, C. Y. Wang, C. C. Tsai, C. L. Chen, Y. T. Chang, J. I. 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

All Science Journal Classification (ASJC) codes

  • Pharmacology

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