INTERLEUKIN-1-BETA AND TUMOR-NECROSIS-FAC TOR-ALPHA ACTIVATE SOLUBLE GUANYLATCYCLASE VIA INDUCTION OF NITRIC-OXIDE SYNTHASE AND INCREASE THE PRODUCTION OF CYCLIC GUANOSIN-3', 5' MONOPHOSPHATE - BIOCHEMICAL ANDFUNCTIONAL EXPERIMENTS IN MESANGIAL CELLS

Treatment of mesangial cells in culture with interleukin-1beta (Il-1be ta) or tumor necrosis factor alpha (TNFalpha) has been shown to increa se cGMP formation, most probably due to induction of nitric oxide (NO) synthase. Here we report that maximum stimulation of cGMP formation o ver a 24 h period required the presence of Il-1beta or TNFalpha during the first 18 h of induction. Treatment of cells with Il-1beta or TNFa lpha markedly attenuated the contractile response of mesangial cells t o a subsequent challenge with angiotensin II. Furthermore, conditioned medium from Il-beta-treated cells increased cGMP in untreated control cells. N(G)-monomethyl-L-arginine was a potent inhibitor of cytokine- induced cGMP formation while N(G)-nitro-L-arginine was less active. Fo rmation of nitric oxide was detected in the cytosol of cytokine-treate d mesangial cells by activation of purified soluble guanylate cyclase, and was stimulated by tetrahydrobiopterin, but not by Ca2+-calmodulin . Excessive NO formation by invading macrophages as well as by activat ed mesangial cells may be responsible for glomerular injury, reduction of glomerular perfusion pressure with a subsequent decrease of glomer ular filtration rate and renal failure.