Advanced glycation end products (AGEs) induce apoptosis via a novel pathway: Involvement of CA 2+ mediated by interleukin-8 protein

Sidharth Mahali, Nune Raviprakash, Pongali B. Raghavendra, Sunil K. Manna

    Research output: Contribution to journalArticle

    36 Citations (Scopus)

    Abstract

    Advanced glycation end products (AGEs) accumulate in diabetic patients due to high blood glucose levels and cause multiple deleterious effects. In this study, we provide evidence that the AGE increased cell death, one such deleterious effect. Methyl glyoxal-coupled human serum albumin (AGE-HSA) induced transcription factors such as NF-κB, NF-AT, and AP-1. AGE acts through its cell surface receptor, RAGE, and degranulates vesicular contents including interleukin-8 (IL-8). The number of RAGEs, as well as the amount of NF-κB activation, is low, but the cell death is higher in neuronal cells upon AGE treatment. Degranulated IL-8 acts through its receptors, IL-8Rs, and induces sequential events in cells: increase in intracellular Ca 2+, activation of calcineurin, dephosphorylation of cytoplasmic NF-AT, nuclear translocation of NF-AT, and expression of FasL. Expressed FasL increases activity of caspases and induces cell death. Although AGE increases the amount of reactive oxygen intermediate, accompanying cell death is not dependent upon reactive oxygen intermediate. AGE induces autophagy, which partially protects cells from cell death. A novel mechanism of AGE-mediated cell death in different cell types, especially in neuronal cells where it is an early event, is provided here. Thus, this study may be important in several age-related neuronal diseases where AGE-induced apoptosis is observed because of high amounts of AGE.

    Original languageEnglish
    Pages (from-to)34903-34913
    Number of pages11
    JournalJournal of Biological Chemistry
    Volume286
    Issue number40
    DOIs
    Publication statusPublished - 07-10-2011

    All Science Journal Classification (ASJC) codes

    • Biochemistry
    • Cell Biology
    • Molecular Biology

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