Our previous experiment confirmed that high mobility group box chromosomal protein 1 ( HMGB1 ) was involved in the pathogenesis of Lupus nephritis ( LN ) by up-regulating the proliferation of mouse mesangial cells ( MMC ) through the cyclin D1/CDK4/p16 system, but the precise mechanism is still unknown. Therefore，in the present study, we demonstrated that HMGB1 induced the proliferation of MMC in time- and concentration-dependent manner, down-regulated phosphatase and tensin homolog deleted on chromosome ten ( PTEN ) expression, increased the level of Akt serine 473 phosphorylation, and induced p65 subunit nuclear translocation. The over-expression of PTEN prevented the up-regulation of HMGB1-induced proliferation by blocking the activation of Akt. The knock-down of Akt by siRNA technology and blocking the nuclear factor-kappa B (NF-B) pathway using pyrrolidine dithiocarbamate (PDTC) and SN50, inhibitors of NF-B, both attenuated the HMGB1-induced proliferation by counteracting the activation of the cyclin D1. In addition, while sh-Akt partly blocked the nuclear translocation of the p65 subunit, PDTC did not affect the activation of the Akt induced by HMGB1 in MMC cells. These findings indicate that high mobility group box chromosomal protein 1 induced the proliferation of mouse mesangial cells by activating the PTEN/PI3K/Akt/NF-B signalling pathway.