OVEREXPRESSION OF PROTEIN-KINASE C-ZETA ISOFORM INCREASES CYCLOOXYGENASE-2 AND INDUCIBLE NITRIC-OXIDE SYNTHASE

Cyclooxygenase (COX) catalyzes the formation of prostaglandins from ar achidonic acid. Nitric oxide synthase catalyzes the production of nitr ic oxide, a short-lived messenger molecule involved in many diverse ce llular processes. Both of these enzymes have inducible forms [COX-8 an d inducible nitric oxide synthase (iNOS), respectively] that respond t o environmental stresses, chemicals, and extracellular ligands such as interleukin-1, epidermal growth factor, and platelet-derived growth f actor. The precise cascade of intracellular events that leads to the e xpression of either COX-2 or iNOS is not known. Protein kinase C (PKC) is a family of II serine-threonine kinases conserved throughout eukar yotic species that transduce a wide variety of signals critical for ce llular functions. Using a retroviral vector to overexpress the zeta-is oform of PKC in rat mesangial cells, we demonstrate markedly increased COX-2, prostaglandin E-2 (PGE(2)), iNOS, and altered cellular morphol ogy compared with mesangial cells expressing a control retroviral vect or and untransfected mesangial cells. NIH/3T3 cells overexpressing PKC -zeta showed no change in morphology, PGE(2) production, COX-2 express ion, or iNOS expression at basal conditions. This suggests a role for PKC-S in the expression of these enzymes in mesangial cells.