The deletion of microsomal prostaglandin E synthase-2 (mPGES-2) does not affect in vivo PGE(2) production, and the function of this enzyme remains unknown until now. This study investigated the expression and roles of mPGES-2 in LPS induced acute kidney injury (AKI) both in vitro and in vivo. We found that mPGES-2 was up-regulated in kidney of mice with LPS induced AKI. Inhibition of mouse mpges2 gene expression exacerbated LPS-induced renal dysfunction, renal tubular cell damage and apoptosis, while inhibited kidney autophagy. Further cellular experiments showed that over-expression of mPGES-2 resulted in increased autophagy and decreased apoptosis rate of renal tubular epithelial cells. In addition, treatment with autophagy inhibitor 3-methyladenine could reverse the above-mentioned results. On the contrary, interference of mPGES-2 expression by siRNA decreased autophagy level but significantly increased apoptosis of tubular epithelial cells and treatment with autophagy inducer rapamycin can reverse these results. Overall, our study shows that mPGES-2 can protect renal tubular epithelial cells by regulating autophagy levels and aggravation of acute kidney injury by mPGES-2 down regulation is associated with autophagy inhibition and enhanced apoptosis.