Activation of AMPK inhibits inflammation in MRL/lpr mouse mesangial cells

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  • A Peairs
    Virginia College of Osteopathic Medicine
  • A Radjavi
    Department of Biomedical Sciences and Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA
  • S Davis
    Department of Biomedical Sciences and Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA
  • L Li
    Department of Biomedical Sciences and Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA
  • A Ahmed
    Department of Biomedical Sciences and Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA
  • S Giri
    Department of Experimental Pathology, Mayo Clinic, Rochester, MN, USA
  • C M Reilly
    Virginia College of Osteopathic Medicine

Description

<jats:title>Summary</jats:title><jats:p>Recent reports show that 5-amino-4-imidazole carboxamide riboside (AICAR), a pharmacological activator of AMP-activated protein kinase (AMPK), inhibits the lipopolysaccharide (LPS)-induced production of proinflammatory cytokines. MRL/MPJ-Faslpr (MRL/lpr) mice show an intrinsic decreased threshold for the production of inflammatory mediators when stimulated. In our current studies, we sought to determine if AMPK activation would inhibit inflammatory mediator production in stimulated kidney mesangial cells. Cultured mesangial cells from MRL/lpr mice were treated with AICAR and stimulated with LPS/interferon (IFN)-γ. AICAR decreased dose-dependently inducible nitric oxide synthase (iNOS), cyclooxygenase-2 and interleukin-6 production in LPS/IFN-γ-stimulated mesangial cells. Mechanistically, AICAR inhibited the LPS/IFN-γ-stimulated PI3K/Akt signalling inflammatory cascade but did not affect LPS/IFN-γ-mediated inhibitory kappa B phosphorylation or nuclear factor (NF)-κB (p65) nuclear translocation. Treatment with the adenosine kinase inhibitor 5′-iodotubercidin blocked the ability of AICAR to activate AMPK and prevented AICAR from inhibiting the LPS/IFN-γ-stimulated PI3K/Akt pathway and attenuating iNOS expression. Taken together, these observations suggest that AICAR inhibits LPS/IFN-γ-induced Akt phosphorylation through AMPK activation and may serve as a potential therapeutic target in inflammatory diseases.</jats:p>

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