The mitogen-activated protein (MAP) kinases mediate the response of renal glomerular mesangial cells to a variety of physiologic and pathologic stimuli. This investigation examines the effect of the cyclopentenone prostaglandin 15-deoxy-Delta (12,14)-prostaglandin J(2) (15d-PGJ(2)) on MAP kinases in human mesangial cells. We show that 15d-PGJ(2) dose dependently increases the extracellular signal-regulated kinase (ERK) activity of human mesangial cells, but has no effect on Jun-NH2-terminal kinase or p38 MAP kinase, Despite the fact that 15d-PGJ(2) is a peroxisome proliferator-activated receptor (PPAR) ligand, and PPAR gamma is shown to be expressed by mesangial cells, the thiazolidinedione PPAR gamma agonist ciglitazone does not activate ERK. Additionally, a synthetic PPAR gamma antagonist does not attenuate the activation of ERK by 15d-PGJ(2). 15d-PGJ(2)-mediated ERK activation is however blocked by the MEK inhibitor PD 098059, appears to require phosphatidylinositol-3 kinase, but is independent of protein kinase C activation. These results demonstrate a novel effect of 15d-PGJ(2) to induce ERK in human mesangial cells independently of PPAR gamma.