HYDROGEN-PEROXIDE DOWN-REGULATES IL-1-DRIVEN MESANGIAL INOS ACTIVITY - IMPLICATIONS FOR GLOMERULONEPHRITIS

In glomerulonephritides, autacoids such as nitric oxide (NO), reactive oxygen species, and prostanoids are produced in increased amounts in response to cytokines such as interleukin-l (IL-1). These autacoids in fluence the expression of glomerular injury by their direct as well as interactive actions. We studied the effect of hydrogen peroxide (H2O2 ) on NO production in rat mesangial cells. We demonstrate that transie nt exposure of mesangial cells to H2O2 prior to sustained exposure to IL-1 decreased extracellular accumulation of NO2/NO3 and cellular guan osine 3',5'-cyclic monophosphate (cGMP) content. H2O2 markedly impaire d inducible nitric oxide synthase (iNOS) activity induced by IL-1 dire ctly measured by the conversion of L-[C-14]arginine to L-[C-14]citrull ine. Such impairment in iNOS activity was accompanied by a parallel re duction in iNOS protein abundance but not by a reduced expression of i NOS mRNA. The inhibitory effect of H2O2 on NOS activity was further su pported by peroxide-induced impairment in IL-1-driven, NO-dependent sy nthesis of prostaglandin E-2. Our studies thus provide the first direc t evidence of a posttranscriptional inhibitory effect of H2O2 on iNOS activity. Additionally, our studies uncover the existence of a previou sly unrecognized effect of H2O2 on the production of NO that may exert influence on the severity of glomerular injury during glomerular infl ammation.