Interaction of MAPK and 12-lipoxygenase pathways in growth and matrix protein expression in mesangial cells.

The lipoxygenase (LO) pathway of arachidonate metabolism and mitogen-activated protein kinases (MAPKs) can mediate cellular growth and ANG II effects in vascular smooth muscle cells. However, their role in renal mesangial cells (MC) is not very clear. ANG II treatment of rat MC significantly increased 12-LO mRNA expression and formation of the 12-LO product 12(S)-hydroxyeicosatetraenoic acid [12(S)-HETE; P < 0.03]. ANG II-induced [(3)H]leucine incorporation was blocked by an LO inhibitor, cinnamyl-3,4-dihydroxy-alpha-cyanocinnamate (P < 0.02). 12(S)-HETE and ANG II directly induced cellular hypertrophy and fibronectin (FN) expression (P < 0.01) to a similar extent. ANG II and 12(S)-HETE led to activation of p38(MAPK) and its target transcription factor cAMP-responsive element-binding protein (CREB). ANG II- and 12(S)-HETE-induced CREB activation and [(3)H]leucine incorporation were blocked by the p38(MAPK) inhibitor SB-202190. A specific molecular inhibitor of rat 12-LO mRNA, namely, a novel ribozyme, could attenuate ANG II-induced FN mRNA. Thus p38(MAPK)-dependent CREB activation may mediate ANG II- and LO product-induced FN expression and cellular growth in rat MC. ANG II effects may be mediated by the LO pathway. These results suggest a novel interaction between LO and p38(MAPK) activation in MC matrix synthesis associated with renal complications.