Cross‐talk between group IIA‐phospholipase A 2 and inducible NO‐synthase in rat renal mesangial cells

Features of glomerulonephritis are expression of the inducible form of NO synthase (iNOS) as well as expression of the secretory group IIA‐phospholipase A 2 (sPLA 2 ) in mesangial cells. Interleukin 1β (IL‐1β) induces both enzymes with a similar time course resulting in an increase in nitrite production and sPLA 2 ‐IIA activity. In this study we investigated the relationship between the formation of NO and sPLA 2 ‐IIA induction in rat renal mesangial cells. Incubation of mesangial cells with the NO‐donor, spermine‐NONOate, for 24 h induced sPLA 2 ‐IIA mRNA expression and activity, whereas S‐nitroso glutathione alone had only a small stimulatory effect. Stimulation of cells with IL‐1β caused a marked increase in sPLA 2 ‐IIA mRNA and activity that were potentiated 3 fold by both NO donors. Coincubation of cells with IL‐1β and the NOS inhibitor, L ‐N G monomethylarginine ( L ‐NMMA), caused a dose‐dependent inhibition of cytokine‐induced sPLA 2 ‐IIA mRNA expression and activity. sPLA 2 ‐IIA activity was not stimulated by 8‐bromo‐cyclic GMP indicating that NO‐induced sPLA 2 ‐IIA induction is independent of cyclic GMP‐mediated signal transduction. These data show that NO contributes to the expression by cytokines of sPLA 2 ‐IIA and establishes a novel type of interaction between iNOS and sPLA 2 ‐IIA in mesangial cells. This cross‐talk between inflammatory mediators may help to promote and sustain an inflammatory state in the kidney.British Journal of Pharmacology (1999) 127 , 51–56; doi: 10.1038/sj.bjp.0702500