In this study, we detected the changes of PIASy, SUMO1, and SUMO2/3; NF-κB-related signaling molecules (IκBα, p-IκBα, p-IKKγ, IKKγ, NF-κBp65, and p-NF-κBp65); and downstream proinflammatory cytokines (MCP-1, IL-6) under high-glucose stress when the rGMCs were transfected with PIASy-siRNA or not, aiming to explore the roles of the SUMO E3 ligase PIASy on NF-κB inflammatory signaling in the pathogenesis of DN. This evidence concerns the gene PIAS4 and liver dysplastic nodule.