Angiotensin II-induced decrease in expression of inducible nitric oxide synthase in rat astroglial cultures: Role of protein kinase C

Inducible nitric oxide synthase (iNOS) has been implicated as a mediator of cellular toxicity in a variety of neurodegenerative disorders. Nitric oxid e, which is generated in high quantities following induction of iNOS, combi nes with other oxygen radicals to form highly reactive, death-inducing comp ounds, Given the frequency of neuronal death due to neurodegenerative disea ses, cerebral:trauma, and stroke, it is important to study the mechanisms o f regulation of iNOS in the brain. We demonstrated previously that angioten sin II (Ang II) decreases the expression of iNOS produced by bacterial endo toxin or cytokines in cultured astroglia prepared from adult rat brain. Her e; we have addressed the mechanisms by which Ang II negatively modulates iN OS, The inhibitory effects of Ang II on lipopolysaccharide-induced expressi on of iNOS mRNA and protein and nitrite accumulation were mimicked by the p rotein kinase C (PKC) activator phorbol 12-myristate 13-acetate, Down-regul ation of PKC produced by long-term treatment of astroglia with phorbol 12-m yristate 13-acetate abolished the inhibitory effect of Ang II on lipopolysa ccharide-stimulated expression of iNOS mRNA and nitrite accumulation. Final ly, the reduction of lipopolysaccharide-induced nitrite accumulation by Ang II was attenuated by the selective PKC inhibitor chelerythrine, Collective ly, these data indicate a role for:PKC in the inhibitory actions of Ang II on iNOS expression in cultured astroglia.