Herein, we focused on the upstream signaling of NF-kB signaling-mediated inflammatory pathway, PI3K/Akt signaling, and found that the persistent hyperglycemia activated PI3K/Akt pathway, which promoted the activation of NF-кB signaling and the release of inflammatory cytokines, subsequently leading to massive proteinuria, tubulointerstitial inflammatory infiltration, mesangial matrix expansion and basement membrane thickening in DKD rats. This evidence concerns the gene NFKB1 and Hyperglycemia.