Platelet-derived growth factor (PDGF)-D is suggested to be a key factor in the development of several renal pathologies, including mesangioproliferative glomerulonephritis. Cyclooxygenase (COX)-2 is a protein involved in the biosynthesis of inflammatory prostaglandins. In this study, we investigated the effect of PDGF-D on the regulation of COX-2 expression in rat mesangial cells (RMCs). Treatment with PDGF-D induced COX-2 at both the protein and mRNA levels in RMCs, suggesting that the PDGF-D-mediated induction of COX-2 is due to COX-2 transcriptional upregulation. PDGF-D treatment also led to a rapid but transient activation of PKB and extracellular signal regulated kinase (ERK)-1/2. Activities of JNK-1/2 and p38 MAPK, however, were not influenced by PDGF-D in RMCs. Markedly, pharmacological inhibition studies showed that pretreatment with LY294002 (a PI3K/PKB inhibitor) or GF109203X (a pan-PKC inhibitor) suppressed the PDGF-D-induced expression of COX-2 protein and mRNA, while pretreatment with PD98059 (an ERK-1/2 inhibitor) or PP1 (an Src inhibitor) had no effect on it. These findings collectively demonstrate for the first time that PDGF-D induces COX-2 by transcriptional upregulation in RMCs and the induction is largely related to PI3K/PKB and PKCs activities.