Figure 8.

Mechanism of hyperglycemia-mediated activation of increased NF-κB and enhanced IGF-I signaling. During hyperglycemia, p62 is increased, which results in PDK1 and PKCζ recruitment followed by PDK1 activation of PKCζ. Activated PKCζ phosphorylates p65 rel Ser311, leading to NF-κB activation, resulting in increased Nox4 expression. In response to IGF-I, Nox4 is recruited to the SHPS-1 signaling complex, where it oxidizes Src. Activated Src stimulates downstream signaling through both the MAPK and PI3K/AKT pathways.