Aldose reductase inhibition prevents lipopolysaccharide-induced glucose uptake and glucose transporter 3 expression in RAW264.7 macrophages

Aramati B M Reddy, Satish Srivastava, Kota Ramana

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Macrophages which play a central role in the injury, infection and sepsis, use glucose as their primary source of metabolic energy. Increased glucose uptake in inflammatory cells is well known to be one of the responsible processes that cause inflammatory response and cytotoxicity. We have shown recently that the inhibition of aldose reductase (AR) prevents bacterial endotoxin, lipopolysaccharide (LPS)-induced cytotoxicity and inflammatory response in macrophages. However, it is not known how AR inhibition prevents LPS-induced inflammation. Here in, we examined the effect of AR inhibition on LPS-induced glucose uptake and the expression of glucose transporter 3 (GLUT-3) in RAW264.7 murine macrophages. Stimulation of macrophages with LPS-increased glucose uptake as measured by using C14 labeled methyl-d-glucose and inhibition of AR prevented it. Similarly, ablation of AR by using AR-siRNA also prevented the LPS-induced glucose uptake in macrophages. Further, AR inhibition also prevented the LPS-induced up-regulation of GLUT-3 expression, cyclic adenosine monophosphate (cAMP) accumulation and protein kinase A (PKA) activation in RAW264.7 cells. Moreover, LPS-induced down-regulation of cAMP response element modulator (CREM), phosphorylation of cAMP response element-binding protein (CREB) and DNA-binding of CREB were also prevented by AR inhibition. Further, inhibition of AR or PKA also prevented the LPS-induced levels of GLUT-3 protein as well as mRNA in macrophages. These results indicate that AR mediates LPS-induced glucose uptake and expression of glucose transporter-3 via cAMP/PKA/CREB pathway and thus represents a novel mechanism by which AR regulates LPS-induced inflammation.

Original languageEnglish (US)
Pages (from-to)1039-1045
Number of pages7
JournalInternational Journal of Biochemistry and Cell Biology
Volume42
Issue number6
DOIs
StatePublished - Jun 2010

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Keywords

  • Aldose reductase
  • CAMP
  • CREB
  • Glucose transporters
  • LPS
  • PKA

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology

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